Ageing

AGING : the chronic-degenerative disease with the longest incubation time; the gradual deterioration in the structure of any organism that occur with the passage of time, that do not result from disease or other gross accidents, and that eventually lead to the increased probability of death as the individual grows older^ref

senescence : the process or condition of growing old, especially the condition resulting from the transitions and accumulations of the deleterious aging processes, which underlie and increasing vulnerability to challenges, thereby decreasing the ability of the organism to survive

dental senescence : deterioration of the teeth and other oral structures as a consequence of advancing age or of premature aging processes

age : the duration of individual existence measured in units of time. 2. the measure of some individual attribute in terms of the chronological age of an average normal individual showing the same degree of proficiency, e.g., achievement age.

achievement age : a measure of achievement expressed in terms of the chronological age of an average child showing the same degree of attainment.
anatomical age : age expressed in terms of the chronological age of the average individual showing the same body development.

bone age : osseous development shown radiographically, stated in terms of the chronological age at which the development is ordinarily attained.

functional age : the combined expression of

calendar or chronological age : the age of a person expressed in terms of the period elapsed from the time of birth.
emotional age : the age of an individual expressed in terms of the chronological age of an average normal individual showing the same degree of emotional maturity.
mental age : the score achieved by a person in an intelligence test, expressed in terms of the chronological age of an average normal individual showing the same degree of attainment.

Binet age : mental age as determined by Binet's test.

physical or physiological age : the age of an individual expressed in terms of the chronological age of a normal individual showing the same degree of anatomical and physiological development.

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developmental age : age estimated from the degree of anatomical development. In psychology, the age of an individual as determined by the degree of his emotional, mental, anatomical, and physiologic maturation.

presenium : age 45-65
senium / old age : age > 65; the period of life marked by the weaknesses and deterioration that may accompany advanced years
senility : 1. old age. 2. the physical and mental deterioration associated with old age.
gerontology : the scientific study of the problems of aging in all their aspects—clinical, biologic, historical, and sociologic (nursing, psychology, sociology, social work, economics, law, and political science)

geriatric medicine / geriatrics : that branch of medicine which treats all problems peculiar to old age and the aging, including the clinical problems of senescence and senility

gerodontics / dental geriatrics / gerodontia : the delivery of dental care to aging persons; the diagnosis, prevention, and treatment of problems peculiar to advanced age

geropsychiatry

Epidemiology : maximum age :

the metazoan with the longest live is the mollusk Arctica islandica, which can live up to 220 years.

Homo sapiens

average life expectancy at birth

super centenarians

Years	Days	Born	Died	Country	Name
122	164	21 Feb 1875	4 Aug 1997	France	Madame Jeanne Louise Calment Traditionally, people who survive one hundred years and beyond are portrayed as having lived hardworking, frugal and disciplined lives. However, Madame Calment came from a priviliged background, never worked, drank a glass of port a day and smoked until 1986. Although she had reduced mobility, poor eyesight and partial deafness, she had no significant cognitive impairment. Details regarding her medical history and geneology are available from demographer Jean-Marie Robine and Micheal Allard of INSERM in France.
120 : Dr. John Wilmoth, has information indicating that the actual longevity of Shigechiyo Izumi may be 105 years and that he assumed the identify of an older brother who died at the age of 15^ref. This may have to do with a Japanese practice of acquiring the name of a dead sibling^ref.	237	(19 ?) 29 Jun 1865	21 Feb 1986 of pneumonia	Japan	Shigechiyo (Chigechiyo) Izumi lived in Asan on the island of Tokunoshima, 820 miles southwest of Tokyo, Japan^ref
116	88	18 Nov 1874	14 Feb 1991	U.S.A.	Carrie White (nee Joyner)
114	213	1 Aug 1877	Mar 1992 (fl)	U.K.	Charlotte Hughes (nee Milburn)
115	245+	16 Aug 1882	25 Apr 1998	U.S.A.	Chris Mortenson
113	124	15 Jul 1701	16 Nov 1814	Canada	Pierre Joubert
112	330	11 Dec 1874	6 Nov 1987	Australia	Caroline Maud Mockridge
112	228	14 Jul 1860	27 Feb 1973	Spain	Josefa Salas Mateo
112		1844	16 Sep 1957	Morocco	El Hadj Mohammed el Mokri
112	+	1868	7 Jan 1981	Poland	Roswlia Mielczarak (Mrs.)
111	354	6 Apr 1745	26 Mar 1857	Netherlands	Thomas Peters
111	327	22 Nov 1820	14 Oct 1932	Ireland	The Hon. Katherine Plunket
111	238	9 Jan 1877	5 Sep 1988	Scotland	Kate Begbie (Mrs.)
111	151	17 Jan 1857	16 Jun 1968	S. Africa	Johanna Booyson
111	+	22 Oct 1857	Oct 1968 (fl)	Czech.	Marie Bernatkova
111		15 Aug 1878	Mar 1990 (fl)	Germany	Maria Corba
111	+	30 Sep 1878	1989	Finland	Fanny Matilda Nystrom
110	321	18 May 1792	4 Apr 1903	Channel Is.	Margaret Ann Neve (nee Harvey)
110	234	10 Mar 1863	31 Oct 1973	N. Ireland	Elizabeth Watkins (Mrs.)
110	150+	9 Mar 1818	Aug 1828 (fl)	Yugoslavia	Demitrius Philipovitch
110	+	1870	19 Feb 1981	Greece	Limbrini Tsiatoura (Mrs.)
110	+	7 Aug 1860	Aug 1970 (fl)	Russia	Khasako Dzaugayev
109	265	4 May 1878	23 Jan 1988	Denmark	Maria Louise Augusta Bramsen
109	179	2 Feb 1836	31 Jul 1945	Tasmania	Mary Ann Crow (Mrs.)
108	327	12 Aug 1868	4 Jul 1977	Belgium	Mathilda Vertommen-Hellemans
108	45	14 Aug 1873	28 Nov 1981	Iceland	Halldora Bjarndottir
108	+	7 Jun 1859	Jul 1967 (fl)	Portugal	Maria Luisa Jorge
106	+	14 Aug 1865	Jan 1972 (fl)	Malaysia	Hassan Bin Yusoff
105	228	31 Dec 1872	17 Aug 1978	Luxembourg	Nicolas Wiscourt

Maria Do Carmo (ne Itajuba), 124 (March 3, 1995), Brazil
Zolfali Soltanmoradi, 140, Iran
Gong Laifa, 147, China
Shirali Mislimov, 168, Caucasus

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the duration of a woman's survival, but not the family size, longevity, or geographical differences, affects both the reproductive success of her children and the survival of her grandchildren

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grandmother hypothesis

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Pan troglodytes : 44 years
Macaca mulatta : 29 years
Felis catus : 28 years
Sus scrofa : 27 years
Rattus norvegicus : 4 years
a sprightly old worm equivalent to a 500-year-old human has broken the record for life-extension. When researchers genetically engineered the worms to switch off a growth protein, and then sliced out their gonads, the worms lived 124 days on average, 6 times longer than normal.

The duration of life seems to be inversely related to proliferation rate. The limiting factor are perennial tissues, where apoptosis are only partly compensated by hypertrophy of remaining cells.
Do all species undergo senescence ? An increase in the age-specific death rate with increasing adult calendar age is one criterion that has been used and the other is decreasing fecundity with increasing calendar age. However, so few species have been assessed for these criteria that an answer to the question of universality cannot be given with anything near certainty. Indeed, rock fish, sturgeons, and carp appear to live to advanced ages without evidence of an increase in age-specific death rates or a decrease in fecundity. However, it is quite possible that these species have not been studied carefully enough to detect such changes if, in these species, they progress at an extraordinarily slow rate. Biologists have long believed that senescence occurs in those species with a germ line that is separate from the soma and that it is only the soma that undergoes senescence : however, recent findings have shown that senescence can occur in organisms that do not have a germ line separate from the soma, such as some species of yeast. Senescence occurs in most, if not all, species that undergo sexual reproduction , including yeasts.
Aetiology : the second law of thermodynamics states that with the passage of time, there is an increase in entropy : living organisms are not closed systems, but rather they are thermodynamically open systems. Specifically, living organisms utilize the matter and energy in food (and light, in the case of photosynthetic organisms) to counter entropy. The maintenance of this complex adult organism would appear to be a far less formidable challenge than its development. Yet even when the supply of external matter and energy is unlimited, it appears that most, if not all, species of complex organisms are not able to prevent deterioration of their structure and function during the adult period of life. Aging is clearly not a thermodynamic inevitability, and yet it occurs widely in nature. Therefore, it must be concluded that the ability to utilize external matter and energy to maintain complex function and structure is progressively lost by most animals and plants with advancing adult calendar age. Why don't evolutionary forces eliminate a process, such as senescence, that is so detrimental to the ability of individual organism to maintain itself and generate progeny ?

extrinsic :

lifestyle : hneybees provide a remarkable example of the influence of lifestyle on lifespan and thus presumably on the rate of aging : female worker bees and the queen bee have very different lifestyles, and even when genetically identical, they have markedly different life spans (2 to 8 months for the workers, about 5 years in the queen).
calorie restriction : in the 1930s, Cornell University nutritionist Clive McCay discovered that rats fed with a balanced diet containig 30% less calories survive about 40% longer or more. The technique works in fish, fleas, and other species, and early data suggest it works in monkeys too. ObR^-/- mice have 50% to 70% less fat than unaltered mice, but they otherwise appear healthy and their median life span increases from about 30 months to 33.5 months : because these animals, despite their leanness, actually eat more than normal mice, the decreased fat tissue produced by calorie restriction, rather than the sparse food intake itself is what is important for greater longevity. In a 2004 study on 42 mice, those with about 30% faster metabolic rates live > 33% longer^ref. If the same is true in humans, this means that people with a speedy metabolism might add an extra 27 years onto a typical 70-year lifespan. This is based on observations that big animals with low metabolic rates, such as elephants, tend to outlive small, high metabolism ones, such as mice: hence the old adage, "live fast, die young". While this overall trend may be true when comparing different species, the new study suggests it may be reversed for animals within one species. The secret to longevity may lie inside mitochondria : they use oxygen to 'burn' food molecules to produce chemical fuel that is used by the cell — but in the process they generate harmful free radicals that damage other molecules and are linked to ageing. Mice with a high metabolic rate have more vigorous UCPs , which cause the mitochondria to generate heat instead of producing fuel. Since more of their energy escapes as heat, the mitochondria have to run at full speed in order to keep generating enough chemical fuel for the cell : at the same time, the mitochondria may run more efficiently and release fewer harmful free radicals, hence slowing the ageing process. Although drugs such as amphetamines are known to speed up metabolism, they may not simultaneously increase the activity of uncoupling proteins, the key to cutting free-radical production and thus potentially prolonging life. In the past, calorie restriction was theorized to be a passive mechanism, whereby fewer calories reduced metabolism and the oxidative stresses that come with it. The protein Sir2—of which SIRT1 is the mammalian orthologue— expression is higher in 12-month-old rats fed a calorie-restricted diet : this finding also extended to in vitro cell culture, with serum from the calorie-restricted rats inducing SIRT1 expression. The addition of insulin and IGF-1 (2 factors known to be involved in extending lifespan) to the calorie-restricted serum blocked the induction of SIRT1. SIRT1 acts on the DNA repair factor Ku70, which was then capable of repressing the apoptosis-inducing protein Bax. This suggested a mechanism in which SIRT1 protects cells from apoptosis. SIRT1 indeed promotes fat mobilization^ref. SIRT1 was found to repress the fat-regulating protein PPAR-g and other genes that drive fat storage following calorie restriction. In addition, the upregulation of SIRT1 in differentiated fats cells caused them to lose fat^ref. SIRT1 is a body defense and survival coordinator for times when food is scare

reduced food consumption, not reduced adiposity, is the important component in extending the longevity of genetically obese (ob/ob) mice^ref

other environmental factors

intrinsic : genetics, not environment, is undoubtedly the major factor for the great differences in the rate of aging among species. Environemnt and gene-environment interactions are also important factors in the differences in the rate of aging among the individuals of a species. Mutations in gametes can decrease or increase the evolutionary fitness of the progeny (so that the mutated allele disappears of become fixed in the population) or be neutral in respect to natural selection (fluctuatin randomly in genetic drift : if they remain in the population, subsequent changes in environment could render these alleles either detrimental or favorable). Individual selection plays a much greater role in biological evolution tha does group selection : individual selection is felt to dominate, whether or not it is of benefit to the species. In 1870 Wallace theorized that after an individual has produced a sufficient amount number of surviving progeny and the ability to generate more progeny is diminished, the individual is still a consumer of resources and is thus detrimental to the progeny. Based on this line of thought, Wallace concluded that natural selection uses aging to eliminate old individuals from the population. In regulating the length of life, the advantage to the species, and not to the individual, is what is important. If senescence did not occur, there would be no point to eliminating the old to make way for the youn, becausethe old and the young would generate progency at the same rate and would not differe in other functional capacity. Thus these early views did not address the quesion of why senescence evolved, but rather provided a possibele explanation of why senescence would be maintained. A second flaw is that these views are based on the concept that senescence is required to eliminate the old to make way for the young. However, for most species in nature, senescence is not required for this purpose. Because of predators, infection, weather, and a host of other environmental hazards, most cohorts in natural populations are reduced to a very low number before senescence has appreciably occurred. Still another flaw is that these views ar absed on group selection or, as stated by Weissman, advantage to the species, which is weak compared to individual selection : since senescence decreases the evolutionary fitness of the individual, natural selection would not be expected to favor it. In 1946 Peter Medawar formulated the current evolutionary theory of aging, based on the fact that the force of natural selection weakens with increasing calendar age. Introducing a hypothetical species that had hitherto been free of senescene, it lives in an environment that is hazardous due to predators, infectious agents, and other hostile environmental factors : it is the progressive decrease in the size of the cohort that undelies the decrease in the force of the natural selection with advancing calendar age. If a deleterious mutation were to be expressed only late in life (i.e. at ages where few if any of the cohort were still alive because of death due to environmental hazards), the mutation would have little or no effect on the number of progeny generated by those with this mutation and thus is would be passed to succeeding generations as effectively as the nonmutated gene. Moreover, under these environmental circumstances, there would be little or no ill effects due to this deleterious mutation, because it would either not be expressed or be expressed in a negligible number of the members of a cohort; i.e., all or nearly all would be dead before it is expressed. However, if a cohort of this species with this deleterious mutation were to be transferred to a protected environment, where most of the population would live to the advanced age at which the mutations is expressed, the deleterious effect would become manifest late in life, resulting in the deterioration of the organism, a condition we call senescence. This hypothetical example illustrates how senescence could develop in a species that previously had not undergone senescence. In species that undergo senescence, 2 additional factors underlie the decrease in the force of natural selection with advancing calendar age. Because of senescence, the vulnerability of the organism to environmental hazards is increased with increasing adult calendar age. In addition, unlike the members of a hypothetical nonaging population, those undergoing senescence have a decrease in fecundity with increasing calendar age. For both of these reasons, under identical environmental conditions, the decrease in the force of natural selection with advancing calendar age will be even greater in a population that undergoes senescence than in a hypothetical nonaging population. Although humans evolved under hazardous conditions and their aging characteristics relate to the circumstances under which they evolved, most human populations are now living under conditions that greatly protect themm from environmental hazards. As a result, most humans live to advanced ages and exhibit advanced stages of senescence, which in many cases reach the point where it is appropriate to use the term senility. Animals that human protect, such as pets, also live to calendar ages at which advanced stages of senescence occur. This is not to imply that senescence does not occur in organisms living in the wild, because even in the wild some of the population of many species live long enough for aspects of the aging phenotype to appear. However, the fraction of the population of most species in the wild reaching extreme old age with a fully developed aging phenotype (ie., senility) is vanishingly small.

estimates of heritability of longevity have varied greatly, from as low as 10% to as high as 70%. Moreover, the validity of using individual longevity as an index of the rate of aging is also open to debate. Thus, at this point in time, the heritability of the rate of aging in humans is not precisely known : some propose genes account for approximately 30% of longevity in humans
in segmental progeroid syndromes (e.g. Hutchinson-Gilford syndrome, Down syndrome and Werner syndrome) not all aspects of the ageing phenotype are accelerated^ref
experimental single gene mutations in species whose genome can be readily manipulated

mutation-accumulation mechanisms (Medawar, 1952) : some of these mutations may not express their deleterious action until late in life, and such mutations will not be eliminated by natural selection because by then the force of natural selection if low to negligible. Such mutations remain in the population and are responsible for senescence because they will be expressed in organisms living in a lifelong protected environment
antagonistic pleiotropy (G.C.Williams, 1957) : gene can have effects that oppose each other. There are genes that have a beneficial phenotypic effect early in life and a deleterious one late in life. Such genes would be strongly selected for because of their beneficial effects early in life when the force of natural selection is great. Moreover, even if their deleterious effects late in life were catastrophic, such genes would not be eliminated from the population because the force of natural selection is weak to negligible late in life. Eg. p53^-/- mice have precocious aging. Senescence can be selected for but in an indirect fashion : it is a byproduct of evolutionary forces

the rate of aging will be slower in populations with higher fertility rates at older ages. This prediction has been tested in laboratory studies using a population of the fruitfly Drosophila melanogaster which researchers divided into 2 groups. One group was allowed to reproduce only at young ages and the other group at older ages. After about 10 years of this procedure (involving > 50 generations for both groups) the late-reproducing group evolved a much longer lived fruit fly than the early-reproducing group. In genetic terms, this study selected for genes beneficial in late life or against those detrimental in late life or both
the rate of aging of a species or subgroup of a species should be strongly influenced by the lvel of hazards in the environment in which the species or subgroup evolved. That is, the rate of aging should be more rapid in those that evolved in highly hazardous environment. For example, species of birds of the same size as species of terrestrial (earthbound) mammals have a slower rate of aging than the mammals; even more impressive is the fact that those species of birds which do not fly or which are poor fliers exhibit the same rate of aging as earthbound mammals of comparable size. The ability to fly makes the environment much less hazardous because it reduces the threat of predation and other dangers such as flood and fire. Indeed, bats (mammals that fly) have a slower rate of aging than earthbound mammals of the same size.
the rate of aging of species living in the same environment should be slower for species of large size than for those of small size because in general, the larger the animal te better it can cope with predators and other environmental hazards. Indeed, there tends to be an inverse correlation between the size of the members of an animal species and the rate of aging of the species.

short life with high reproductive ratio
long life with low reproductive ratio

sodium retention (once rare in environment) nowaday may predispose to systemic arterial hypertension
calorie retention (once advantageous) nowaday may predispose to obesity and type 2 diabete mellitus

^{ref1,
ref2,
ref3}

SIRT1 : caloric restriction promote the survival of human cells and extend the replicative lifespan without reducing fecundity via Sir2 (a member of the sirtuin family of NAD⁺-dependent deacetylases activated by sirtuin activating compounds (STACs), e.g. resveratrol ) in the budding yeast Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster^ref
abnormal DAuer Formation (DAF-2)
p66^SHC1
ctl-1
amin A
age-1
CLOCK
Methuselah GPCR in Drosophila : 2 endogenous peptide ligands are designated Stunted A and B. Flies with mutations in the gene encoding these ligands show an increase in lifespan and resistance to oxidative stress^ref
I'm Not Dead Yet (Indy) : a transporter for citrate and succinate. Decreased activity leads to decreased metabolism and ROS.
SOD1
C150T transition in mtDNA occurs in 17% of the human centenarians, while just 3.4% of non-centenarians have the mutation. While in some the mutation is inherited, in others it appeared or become more abundant over time.
BubR1 : mutant mice with low amounts of protein live 5 times shorter than normal mice and develop cataracts that are very similar to age-related cataracts in humans
cholesteryl ester transfer protein (CETP) : in a study on 300 Ashkenazi Jews between 95 and 108 years old and their children, many of whom themselves have lived beyond the average life span - 77.6 years, CETP was present in 8% of 65-year-olds. The incidence jumped to 25% in those who made it to 105. CETP regulates lipoproteins, which shuttle cholesterol and triglycerides through the bloodstream. CETP increases the good form of cholesterol, HDL. Those who inherited this rare form also showed no signs of dementia, seen in 50% of people over 85.
Zmpste24 / FACE-1 is a metalloproteinase involved in the maturation of lamin A (Lmna), an essential component of the nuclear envelope. Both Zmpste24- and Lmna-deficient mice exhibit profound nuclear architecture abnormalities and multiple histopathological defects that phenocopy an accelerated ageing process. Similarly, diverse human progeroid syndromes are caused by mutations in ZMPSTE24 or LMNA genes. Zmpste24 deficiency elicits a stress signalling pathway that is evidenced by a marked upregulation of p53 target genes, and accompanied by a senescence phenotype at the cellular level and accelerated ageing at the organismal level. These phenotypes are largely rescued in Zmpste24^-/-Lmna^+/- mice and partially reversed in Zmpste24^-/-p53^-/-mice. These findings provide evidence for the existence of a checkpoint response activated by the nuclear abnormalities caused by prelamin A accumulation, and support the concept that hyperactivation of the tumour suppressor p53 may cause accelerated ageing^ref.
catalase : median and maximum lifespans were maximally increased (average 5 months, and 5.5 months, respectively) in transgenic mice that overexpress human catalase localized to the mitochondrion (MCAT). Cardiac pathology and cataract development were delayed, oxidative damage was reduced, H₂O₂ production and H₂O₂-induced aconitase inactivation were attenuated, and the development of mitochondrial deletions was reduced. These results support the free radical theory of aging and reinforce the importance of mitochondria as a source of these radicals^ref
genes encoding components of the nutrient-responsive TOR and Sch9 pathways increase replicative life span in the budding yeast Saccharomyces cerevisiae. Calorie restriction of tor1D or sch9D cells failed to further increase life span and, like calorie restriction, deletion of either SCH9 or TOR1 increased life span independent of the Sir2 histone deacetylase. The TOR and Sch9 kinases define a primary conduit through which excess nutrient intake limits longevity in yeast^ref

The extent of the increase in risk of mortality is assessed by determining the increase in age-specific death rate with increasing calendar age = the fraction of the population of a given age that dies during a time interval. The increase in the age-specific death rate with advancing calendar age is an index of increasing vulnerability due to senescence. A cohort is a group of individuals that share a statistical characteristic. In the case of the animals in gerontologic laboratory studies, a cohort usually refers to individuals born during a particular period of time.
In addition to an increasing risk of mortality, many anatomical and physiological changes occur (mostly deteriorative) : the extent to which such changes are the result or the cause of the age-associated increase in vulnerability or organisms is not known and undoubtedly varies with the particular anatomical or physiological change. There is a great deal of individual variation in the occurrence and the magnitude of age changes in anatomical structures and physiological systems. Most elderly people do exhibit substantial deterioration in many physiological systems, reducing ability to cope with challenges and functional capacity. Age-associated diseases are those that occur only at advanced ages or are more prevalent in the old : cancers primarily occur after 2 years of age in rats, while in humans they occur mostly after 50 years of age. Moreover, each species has a set of age-associated diseases that differ from those found in other species. In humans, the increases in morbidity (a disease state) and mortality due to coronary heart diseases, stroke, type II DM, osteoporosis, Alzheimer's disease, Parkinson's disease, and prostatic cancer relate to calendar age in a fashion similar to that of the increase in age-specific death rate. Although multiple sclerosis, amyotrophic lateral sclerosis, gout, peptic ulcer, and most cancers are aso age-associated, their occurrence does not parallel the increase in age-specific death rate.
Pathogenesis : the general pattern of aginig appears to be similar for most mammalian species. In no case has supporting evidence been sufficient to justify using the word "theory"; "hypothesis" would be he more appropriate term. Since senescence probably stems from many different proximate mechanisms and their interactions, strong evidence in support of a single mechanism seem highly unlikely. Most of the poposed mechanisms are based on a particular characteristic of the aging phenotype : unfortunately, it is difficult to know whether such a characteristic plays a causal role in senescence or is rather the result of senescence^{ref1,
ref2,
ref3,
ref4,
ref5}. Somatic cloning bypasses the selection mechanisms acting on gametes => high mortality and low life expectancy in newborns.

how aging occurs

~~evolutionarily adaptive aging clocks~~ in a fashion similar to the programming of the development of the organism from conception to young adulthood. If the evolutionary theory of aging is correct, senescence is not the result of adaptive selection, but rather, at most, is a byproduct of evolution, so the aging clock theory is not compatible with currently held concepts of the evolutionary biology of aging. However senescent deterioration during adult life is clearly influenced by genetic characteristics. Developmental processes that increase early-life fitness are strongly favored by natural selection, even if those processes are detrimental in late life, thereby becoming a cause of senescence; i.e. the genetic process of antagonistic pleiotropy could link development and senescence in a clocklike manner In addition, in a general sense, developmental processes play an important role in determining the vulnerability of the fully developed adult to damaging challenges, including those involved in senescence. Thus, there clearly are links between development and senescence. In conclusion, it seems warranted to discard the concept of evolutionarily adaptive aging clocks per se.
inability to completely repair wear and tear theories focused on the wearing out of gross structures, such as the erosion of teeth of herbivores. An elephant develops a new set of molars at 6 separate times at about 10-year intervals during its life, and thus for about 70 years, it replaces molars as they wear out. Nevertheless, with advancing age, repair processes fail to keep up with wear and tear : most current theories are focused on cellular and moleculr deterioration, rather than directly on deterioration of gross structures

rate of living theory : in 1928 Raymond Pearl proposed that organisms are born with a specific amount of vital principal that is irreplaceable and is depleted at a rate proportional to the rate of energy expenditure (metabolic rate). As early as 1908, Max Rubner postulated that the longevity of mammalian species inversely relates to the rate of energy expenditure per kilogram of body weight. At this time, it appears unlikely, that metabolic rate per se plays a major role in aging. The benefit of restricted feeding regimens are reversible in rats and appear only if the regimen has been started before months 12 of age (with effectiveness decreasing if started after 6 months of age). Anyway the regimen restricted to 60% of daily ad libitum causes approximatively 6 hours of feeding and 18 of starvation, during which catabolic autophagy allows the renewal of the cytoplasm, including organelles, an additional reason for increasing longevity. Organelle renewal also explains the late penetrance of mitochondrial myopathies. Common deletion is explained by assuming the anchroage of such a region of the mitochondrial chromosome to the inner mitochondrial membrane (as occurs in bacteria) and then the higher proximity to the ROS-generating sites. Changes in [ROS] can be induced by administrating competitive inhibitors of cCPK, which indirectly stimulate oxidative metabolism. Without organelle renewal the difference between the accumulation of mitochondrial lesions in unrestricted and restricted feeding regimens would be greater. The same difference at nuclear level obviously cannot be explained by autophagy, but only with apoptosis and necrosis (which also contribute to the difference at the mitochondrial level)
free radical theory : in 1954 Denham Harman reasoned that alterations in the structure of DNA molecules, due to free radical attack could be a cause of aging. Although present in organisms at low concentrations, free radicals are continuously being generate by a variety of important cellualr processes, and among these is fuel utilization (see ROS and AGE)
oxidative stress hypothesis : oxidative metabolism involves a series of chemical steps which, in addition to generating ATP, yield carbon dioxide and water as the primary end-products of the reactions between the dietary fuels and molecular oxygen. Reaction of ROS generates an array of additional ROS : some 2-3% of the molecular oxygen used by anaerobic organisms generates superoxide radicals and H₂O₂, which can

alter the structure and function of genes
cause carbonylation of proteins and loss of sulfhydryl groups, thereby altering enzymatic and other functional activities of proteins as well as increasing susceptibility of these molecules to proteolysis and thus loss of function
peroxidize the PUFA components of membrane lipids

enzymes
antioxidant compounds (e.g. vitamins A, C, and E)

glycation and glycosylation hypothesis of aging, proposed in 1985 by Anthony Cerami focuses specifically on carbohydrate fuel (reducing sugars : starch, table sugar, and milk sugar). Diabetes mellitus , in which more AGEs are accumulated due to higher concentration of glucose in body fluids, is a condition of accelerated aging. The presence of AGE on molecules of collagen contributes to atherosclerosis, thickening of the basement membrane of the kidney, peripheral vascular occlusions, and Alzheimer's disease. Too, there is evidence that the amino groups of the DNA bases can also undergo glycation. An oxidatve pathway can also be involved in the glycation of macromolecules (glycoxidation hypothesis of aging, proposed by Bruce Kristal and Byung Paul)
inadequate protein turnover : the primary cause of aging is not the inevitabledamage, but rather the inadequate ability to get rid of old protein molecules and replace them with new. There is evidence that with increasing age calendar age, many species of proteins show a slowing in the rate of turnover, allowing levels of altered, malfunctionin protein molecules to accumulate in the organism
altered biological membranes (site of information input from the nervous system, endocrine system, and other sources, and in cellular organelles, such as in the generation of ATP by mitochondria) : peroxidative damage of membrane lipids does occur with increasing calendar age. In addition, and possibly more importantly, the ratio of saturated to unsaturated fatty acids in the membrane is known to increase with increasing age.
altered extracellular matrix : because mature collagen and elastin molecules turn over very slowly, oxidation, glycation, and other nonenzymatic events gradually change the functional characteristics of these structural proteins by forming complex cross-links and other structural alterations with advancing calendar age, lessening distensibility and mechanical strength

genes and gene expression :

accumulation of mutated genes with deleterious action occurring late in life
antagonistic pleiotropic gene expression

somatic mutation theory (Leo Szilard, 1959) : even sub-lethal radiation almost always shortens the life span of mammals. Medawar's concept of the accumulation of mutated genes whose deleterious consequences are expressed only in later life refers to inherited genes, which are present in all the nucleated cells thorughout the life span of the organism. In contrast, Szilard's concept is based on the generation of mutations in individual somatic cells during the life span of the organism (random aging hits), leading to the death of the organism when a sufficient number of cells become dysfunctional. Chromosomal DNA is continuously being damaged by a variety of causes, both endogenous and exogenous factors : there are 10,000 hits per cell per day. However, repairs do not quite keep up with damage and, as a result, there is an increase in the level of chromosomal DNA damage with increasing calendar age (ie, DNA suffers from wear and tear). Thus the question to be answered is not whether damage to DNA increases with age, but rather if enough somatic cells are sufficiently damaged to cause significant organismic dysfunction. Moreover, damaged cells, including those with damaged DNA, are eliminated by apoptosis. There is a decrease in apoptosis with advancing age and by allowing damaged cells to accumulate in the organism, this decrease in apoptosis could be a cause of senescence. On the other hand, a loss of even damaged cells could be a cause of senescence and if so, the decrease in apoptosis with advancing age could be a factor retarding senescence. Although the currently available information does not enable us to assess the importance of somatic mutations in senescence, there is one aspect of the aging phenotype that may well be the result of somatic mutations, and that is the age-associated increase in the occurrence of cancers.
concept of mitochondrial DNA damage : mitochondrial DNA is in close proximity to the mitochondrial sites of ROS generation, unlike the chromosomal DNA and would undergo more oxidative damage. Moreover, the nucleus has well-developed DNA repair systems, while such systems in the mitochondria appear to be less effective. Indeed, it has been shown that mitochondrial DNA accumulates more damage than does chromosomal DNA. The highest levels of damage to the mitochondrial DNA are found in the cells of highly oxidative organs in which little or no cell division occurs, such as heart, brain, and skeletal muscle, playing a major role in senescence by interfering with the ability of the cells to generate sufficient amounts of ATP (some of mtDNA genes code for proteins involved in the oxidative processes that occur in the mitochondria). The evidence pointing to a major role of altered mitochondrial DNA in senescence is weak. Those cells whose mtDNA is very damaged may then be eliminated by apoptosis, thereby decreasing the accumulation of damaged mtDNA in an organ but at the cost of losing cells; indeed, those tissues and organs with the greatest mitochondrial damage with advancing age are also those that tend to lose the most cells with advancing age.
telomere senescence theory : the loss of telomere DNA, which occurs each time a cell divide in renewing tissues, is a clear example of the wear and tear at the molecular level. In 1961 Hayflick and Moorhead reported that fibroblasts divide only about 50 times in vitro. It appear to be a property of all normal somatic cels in culture and is now known as the Hayflick limit, expressed as the number of times in which plaque confluence is achieved and not as number of cell cycles (which is then > 50). The phenomenon of limited cell proliferation in culture is an in vitro model of aging and therefore a vehicle for the experimental study of aging. Anyway the evidence that this in vitro system is pertinent to organismic aging is weak as in vitro is a pro-aging environment due to complete lack of a lipid-removing system and discontinuous removal of hydrosoluble catabolytes (on the contrary of the continuous filtration by the kidneys in vivo, culture medium is removed only sporadically). As intestinal stem cells make > 5,000 rounds of replication in the life of an individual and plaque confluence involves < 100 rounds, the number of cycles is higher in vivo. This theory proposes that the shortening of telomeres is responsible for the limited number of mitotic divisions that somatic cells undergo in culture. Thus telomere shortening is viewed as the way the cell "counts" the number of divisions it has undergone. The germ cells and most tumor cells (both of which have an unlimited capacity to divide in culture) have an enzyme called telomerase which promotes the extension of telomeres, thereby countering the shortening of telomeres during mitosis. Somatic cell division in vivo also results in shortening of the telomeres. The shortening of telomeres leads to such aging problems as inadequate wound healing, immune dysfunction, and age-associated cardiovascular disease. It is equally plausible that the "Hayflick limit" of somatic cell proliferation may be a mechanism that evolved to protect organisms from developing cancers. Telomeres shrink dramatically in patients who are obese or heavy smokers : shorter telomeres mean you will run out of steam sooner than people with longer ones. Obese women in the study were, according to their telomeres, 9 years 'older' than slim women of the same age. Heavy smokers, who consumed a pack a day for 40 years, showed 7 years of extra biological ageing. Researchers already knew that smoking and obesity could cause a kind of stress in cells that produces reactive chemicals, which in turn are known to wear away telomeres. Spector's large study looks directly at this effect to quantify just how much a cigarette can age you. Spector's team collected information and blood samples from > 1,100 women aged between 18 and 76 years. Within this group, 11% had a BMI > 30, which classified them as clinically obese. About 18% were active smokers. The researchers sequenced the DNA of the women's white blood cells to find the length of their telomeres. Overall, they found that a woman's telomeres shorten by about 27 bp a year; a base pair being a single letter of DNA in your genetic sequence. But heavy smokers wore an additional 200 bp off their telomeres after 40 years of puffing. And obese participants' telomeres were, on average, 240 bp shorter than those of their lean counterparts. This ageing effect might help to explain why these women are at a greater risk of age-related health problems such as heart disease. But it is important to note that the whole body ages faster under this kind of stress, not just the heart. The immediate impact of such ageing could provide a different motivation to quit smoking or start a diet, alongside the fear of one day contracting cancer or heart disease. People do distinguish between growing older and dying earlier. The research team now plans to examine the effects that exercise, diet and occupation have on telomere length^ref.

Web resources

concepts based on altered gene expression :

in 1961, Zhores Medveded was the first to postulate that errors in information transfer from DNA to proteins may underlie senescence. In 1963, Leslie Orgel proposed the error catastrophe theory, which posits that if an error is made in the formation of a protein involved in the transcription or translation processes, this defective protein (i.e. a protein with an error in its amino acid sequence) would cause the generation of other proteins with errors, including proteins involved in transcription and translation. Indeed such mutations occur infrequently
the dysdifferentiation theory of aging posits that with increasing age some of "turned off" genes are "turned on", resulting in the cell generating species of proteins that are not needed, thus disturbing the functioning of the specialized cell, but little change is actually found

regulation of systemic function : it has been proposed that aging is not due to major changes in the functioning of most cells, but rather to a small change in the functioning of specific cells involved in the integrated systemic functioning of the organism. The proximate mechanisms of senescence may stem from the loss of precision in organismic regulatory functions, then causing widespread changes in the functions of many, if not all, cells of the organisms

endocrine and neural regulation : senescence could be due to a hormone deficiency. The similarity noted between elderly people and patients with hypothyroidism is only superficial. Deficiency of GH, estrogen, melatonin, and DHEA of their receptors and STPs have been proposed. The glucocorticoid cascade hypothesis of aging proposed by Robert Sapolsky and his associates in 1986 postulates that glucocorticoids play an important role in the ability of the organism to cope with both physical and psychological stress; but when present at concentrations that are too high, glucocorticoids can cause widespread damage. Nerve cells in hippocampus sense the level of plasma glucocorticoids, and if the level is too high, they send information via nerve impulses to the hypothalamic-pituitary system to decrease the rate of glucocorticoid secretion by the adrenal cortex, in a negative feedback system. Encountering stress is an inevitable fact of life, and that the resulting high levels of glucocorticoids tend to damage nerve cells in the hippocampus, particularly with the simultaneous occurrence of another insult, such as a decreased flow of blood to the hippocampus. Some of the hippocampal neurons die, and this compromises the effectiveness of the negative feedback system : increase in the plasma glucocorticoids to very high sustained levels, which causes the widespread damage characteristic of senescence, such as impairment of the immune system, loss of bone mass, and impaired cognition. Indeed glucocorticoids increase with increasing age in rats, leading to a loss of nerve cells in the hippocampus
altered immune function : with advancing age, the ability to discriminate between self and non-self tends to become faulty and, in some people, can lead to autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and glomerulonephritis, and autoimmune hemolytic anemia. Changes occur with age because of somatic mutation or some other alteration (e.g. crosslinking of macromolecules), and these changes result in inappropriate cell interactions. Although autoimmune diseases increase with advancing age, there is no evidence for the occurrence of more subtle loss in self-recognition.

The disposable soma theory of aging proposed by Thomas Krkwood postulates that the besic function of all organisms is to utilize free energy in the enviroment to produce progeny : to do so requires that a portion of the energy be used for the maintenance of the organism. The force of selection acts to apportion the use of energy between reproduction and somatic maintenance in a fashion that tends to maximize evolutionary fitness : less energy is used for somatic maintenance than is required for indefinite survival - and thus the occurrence of senescence

in the case of those that evolved in a highly hazardous environment (predation, infection, etc.), the greatest yield of progeny would be achieved when relatively little energy is invested in somatic maintenance, enabling such organisms to reproduce at high rates at young ages : if such organisms are then placed in a protected environment, they will undergo rapid senescence and for that reason will have a short life span, albeit longer than it would be in the wild.
for species that evolved in protected environments in the wild, it is postulated they apportion a considerable amount of energy to somatic maintenance, have a modest rate of reproduction which, however, continues past young adulthood, and have a long life span in the wild, which becomes even longer if placed in a more protected environment than the one in which they evolved.

The proximate mechanism of aging should be divided into 2 classes : the "private" category refers to mechanisms that are idiosyncratic to certain lineages, populations, or species, while the "public" category refers to mechanisms generally operational among a diverse group of species. This classification addresses the apparent paradox that while senescence exhibits general similarities among a broad range of different species, there are many specific differences in the aging phenotype of various species and, indeed, among members of the same species. Mutations with deleterious late-life actions will most likely be in the private category, based on the fact that such mutations are neutral in regard to natural selection, neither favoring nor disfavoring evolutionary fitness in young adults. Since genetic drift determines their presence, their occurrence would be expected to vary among lineages. Examples include the ones that cuase Huntington's disease and the e4-allele of apolipoprotein E locus (found in approximately 15% of European adults) which increases the risk of coronary heart disease and late-onset Alzherimer's disease. This view should be broadened to include all traits that have a detrimental action expressed at advanced ages, rather than being restricted solely to well-defined mutations. For example, essentially all humans show a progressive bone los with advancing age, which appears to be a species genetic trait (and thus a private mechanism) since it does not occur in most mammalian species. Second, it seems likely that antagonistic pleiotropy can also be involved in "private" mechanisms. Indeed, the male sex hormone, so importantly involved in young men generating progeny, has been implicated inn the late-life occurrence of prostate cancer and coronary heart disease, a clear example of antagonistic pleiotropy. Public mechanisms are most likely to be associated with antagonistic pleiotropic genes as there are a relatively small number of processes in which functions are beneficial in early life and harmful in late life, and such genes will be maintained by strong selective forces andtherefore are likely to spread widely among individuals and species. Such genes have yet to be clearly identified : antagonistic pleiotropy, in so far as it occurs, is likely to primarily underlie private mechanisms of senescence. "Public" mechanisms are likely to be in the domain of the disposable soma theory : accumulation of damage occurs in all organisms that undergo senescence.

the underlying causes of aging in the sphere of the public mechanisms are the numerous and varied long-term, low-intensity stressors that are inevitably encountered by an organism during its life. Do we know the nature of the intrinsic processes that cause low-intensity, long-term stress? Probably many are known, but further work is needed to identify and establish them as stressors causing aging.

the organism's use of oxygen
glycation or glycoxidation resulting from the use of carbohydrate fuel
infectious agents
thermal insults
polluttants
environmental factors may often play a more important role than intrinsic factors

private mechanisms are variety, with particular ones occurring only in some species or some individuals within a species They involve genes with deleterious actions that become manifest only late in life, leading to age-associated diseases. The genetic makeup of the organism results in the stressor producing the unique kind of damage that is characteristics of the particular disease.

In the classical view, senescence is deemed an entirely intrinsic process; and second, age-associated iseases are not considered a part of "normal" aging. If senescence, results from the long-term accumulation of unrepaired damage, it is immaterial wheteher the damage is caused by intrinsic processes or by extrinsic (environmental) factors. Extrinsic agents cause damage by interacting with biological materials and activities; and in this sense, all damage is intrinsic. Environmental factors are often the most important factors underlying senescence. The very old invidiual, free of discernible disease, is nevertheless recognized as frail; arbitrariy, that fraility is referred to as physiological deterioration, and thus, according to the classical view, the person has undergone "normal" aging, i.e., aging in the absence of a disease. The elderly person whose physiological deterioration is recognized by a physician as due to an age-associated disease and the elderly person whose physiological deterioration is recognized only as old age are both experiencing the effects of senescence. Senescent deterioration in humans is primarily a function of lifestyle. "Private" mechanisms play a dominant role in human aging; however, "public" mechanisms, such as oxidative stress, may well be involved in these "private" mechanisms. Each spescies must be assessed separately because it is clear from the available information that the aging of each species is, in some way, unique to that species^{ref1,
ref2,
ref3}.
Symptoms & signs : although some of the age changes in anatomical and physiological characteristics may be a cause of senescence, most are probably the result of it. Some phenotypic changes may have little to do with organismic senescence. For example, there is no evidence that graying of the hari increases a person's vulnerability or decreases the ability to function. Thus, although associated with advancing calendar age, graying of hair probably does not belong in the category of senescence.

microscopic anatomy :

senescence-associated heterochromatic foci (SAHF) are chromosomal regions that contain genes switched on in proliferating cells, but are switched off or "silenced" during cellular senescence, and whose formation is mediated by Rb
DNA damage may reduce the expression of selectively vulnerable genes involved in learning, memory and neuronal survival, initiating a programme of brain ageing that starts after age 40^ref

body structure and composition

height : by age 70, the height of men and women is some 2.5% to 5% below its peak level. This decrease begins at about age 25 in men and age 20 in women. In a longitudinal study in which people in the age range of 55 to 64 were followed for the next 11 years, the average loss in height was 0.5 inch for men and 1 inch for women. The loss of height is due primarily to the compression of the cartilaginous discs between the vertebrae and to a loss of vertebral bone
body mass, commonly referred to as body weight, increases in most African men from age 20 until middle age, followed by a decline at advanced age, particularly after age 70. For most American women, weight increases from age 20 to 45, after which it remains stable until about age 70 and then declines with increasing age.

lean body mass, which is higher in men than in women, declines by about 0.3% per year in men and 0.2% per year in women during adult life, due to the loss of muscle mass, but a loss of bone and other structures is also involved (more sedentary lifestyle, but occurs in even in athletes)
fat mass percentage content increases with increasing age both subcutaneously and in abdominal viscera due to an increasingly sedentary lifestyle with advancing age : those who continue as athletes into advancing ages have a smaller increase in body fat content, but even in these people, some increase does occur. There is also a change in distribution, with fat tending to accumulate in the abdominal region, primarily around the viscera, in both sexes, though it is greater for men than for women, a risk factor for age-associated cardiovascular disease. Physical activity retards the age-associated distribution.

cellularity

cell atrophy and loss : total intracellular water decreases, due to both a decrease in the number of cells and in the size of cells, with particular cell types involved at specific anatomical site
hypertrophy (e.g. of cardiomyocyte) and hyperplasia (e.g. of prostate cells) may cause functional problems
neoplasia increases with increasing age

extracellular matrix experiences loss in tensile strength as well as a decrease in compliance (distensibility) and elasticity (resiliency)

specific organ systems

skin :

intrinsic aging of the skin : in nonsmokers, there are age changes that occur in the skin areas protected from exposure to the sun

the thickness of the barrier of flat keratinocytes at the surface of epidermis does not change with age, but the rate of shedding these cells decreases, as does their rate of replacement, so that these cells remain longer at the surface of the skin.
the number of melanocytes decreases with increasing adult age, so that if exposed to sunlight the skin is less protected from UV.
Langerhans cells decreases by 20-50%, increasing susceptibility to skin cancers. The structure of the basement membrane alters, decreasing the extent of interaction between the dermis and epidermis
the thickness of the dermis is about 20% less in the elderly, making it more vulnerable to injury. There is an age-associated decrease in collagen and alterations in the structure of elastin
there is adecrease with age in the small blood vessels of the dermis
reduction in the number of hair follicles
reduction in both the number and functional capacity of the sweat glands => difficult thermoregulation
the ability of the sebaceous glands to secrete sebum is decreased
subcutaneus fat increases with advancing age in some regions of the body, such as waist in men and the thighs in women; it decreases in other regions, such as the face (=> facial changes), hands, shins, and feet

extrinsic aging of the skin :

photoaging : chronic photodamage is estimated to cause > 90% of age-associated skin cosmetic problems by damaging elastin and collagen. It leads to coarseness of the skin, dilation of groups of small cutaneous blood vessels, irregular pigmentation, and deep wrinkles. It also causes a decrease in the number of epidermal Langerhans cells
smoking : benzo[a]pyrene, CO, and nicotine (not mutagenic?) promote wrinkling of the facial skin, with a synergistic action with sun exposures

age changes in skin physiology : the loss of body water through the epidermis is decreased with increasing age and there is a decrease in the ability of substances to enter the body through the skin. The decrease in the number of Langerhans cells leads to less vigorous delayed hypersensitivity reactions to common antigens, such as those of candida and mumps. There is also a decrease with advancing age in immediate hypersensitivity reactions in areas not exposed to the sun : however, in sun exposed areas, allergic reactions may be increased, because photoaging increases the number of mast cells in the dermis. The inflammatory response is less intense, making older people more susceptible to harm from noxious substances. All stages of wound healing are impaired. After age 30 there is an exponential increase in the incidence of skin cancer with increasing age. About 90% of these skin cancers occur in the approximately 10% of the skin that is habitually exposed to the sun. People over 70 account for 70% of those with decubitus ulcers or bedsores (erythema => loss of epidermal and dermal structures => full-thickness skin loss and tissue necrosis) due to prolonged pressure on a particular area because of reduced motility (prolonged periods in bed are more common in elderlies) : additional factors are friction and moisture, particularly moisture due to urinary and fecal incontinence.
geroderma / gerodermia : dystrophy of the skin and genitals, producing the appearance of old age

geroderma osteodysplastica / Walt Disney dwarfism : a condition believed to be transmitted as an autosomal recessive trait, in which geroderma is associated with osseous changes, including osteoporosis and lines in the bones somewhat resembling growth rings of a tree

geromarasmus : the emaciation sometimes characteristic of old age
geromorphism : premature senility

cutaneous geromorphism : a condition in which the skin shows at a very early age the characteristics of old age

musculoskeletal system :

the number of fibers in skeletal muscles varies among different muscles, ranging from < 100,000 to > 1,000,000. The lengths of muscle fibers also vary up to 30 cm. A decrease in skeletal muscle mass (sarcopenia) occurs in many, but not all, skeletal muscles, leading to a decrease in muscle strength between 30 and 80 years of age by about 30% for te arm muscles and about 4% for the back and leg muscles. With the decrease in muscle force, there is a decrease in muscle power output (P = L/t = (F ^. s)/t = F ^. v). Disuses due to a more sedentary lifestyle will lead to a decraese in muscle fiber size as well as a change in functional characteristics. 70-year-old men who have been physically active or have undergone strength training can develop a muscle force as great as sedentary young adults. This stems from developing an increased muscle fiber size to compensate for the reduced number of fibers
neuromuscular functions : with increasing adult age, there is a loss of motor neurons. Most, but not all, of the denervated muscle fibers subsequentially receive axon branches from the remaining neurons and are said to be reinnervated. At least in part, the loss of skeletal muscle cells with increasing age is secondary to denervation. Larger motor units reduce the ability to carry out fine movements.
bone : with advancing adult age, the balance during remodeling shifts in favor of bone resorption, which affects all bones in the skeleton to varying degrees. Bone loss is greater in women than in men, and the rate of loss accelerates in women after menopause due to low levels of estrogens. This rate of bone loss is most rapid during the 10 years following cessation of menses and slows after that. Bone loss in the legs and arms does not occur until the sixth decade. Men start to lose bone at later ages than do women, and in some men, the amount of loss is trivial. This leads to osteoporosis .
joints : osteoarthritis , rheumatoid arthritis , gout

nervous system :

general nervous system age changes : brain weight decreased by up to 15% since age 55; gray matter atrophy (since age 60) => white matter atrophy (since age 70), enlarged and deepened sulci, dilated ventricles, flattened gyri, fibrotic and calcified dura mater and leptomeninges; microscopic anatomy : -10-20% neurons at age 80 (-40% at age 90) expecially in smaller neurons of frontal and temporal regions; decreased dendritic arborization, neuronal degeneration, < 12 senile plaques/microscopic field, NFT in hippocampus only, Chardin's marginal gliosis (increased glial fibrils in the molecular layer of the cerebral cortex). The brain weight of young people who died in 1870 was less than that of the same age who died in 1970. Thus clearly there is a cohort effect, which points up the difficulty of determining how much of the difference reported for brain weifht of the old and the young is due to age and how much a cohort difference. This interpretational problem would be eliminated if brain weight could be measured at different times during the life of an individual. Of course, it is not possible to weigh the brain of a living person. However, modern brain imagin technology enables the measurement of the volume of the brain (a good surrogate for weight) in the living individual. Based on cross-sectional studies using imaging technology, it appears that the brain makes up about 90% of the cranial cavity until about age 50; after that, with advancing age, it occupies a progressively smaller percentage of the cranial cavity. An increase in volume of the cerebrospinal fluid in the ventricle is about the same magnitude as the reduction in brain volume. Most experts agree that there is little generalized age-associated loss in neurons, although some localized brain regions do suffer substantial loss. Rather than generalized neuron loss, there is neuron atrophy. The number of several types of glical cells increases with adult age;however, in one type, there is an increase in cell size rather than an increase in number of cells. The number and complexity of dendritic projections from neurons decrease with increasing age, and this results in a decrease in the number of synapses : people of age 75 have about 20% fewer synapse than those of age 40. There appears to be little change in blood flow to the brain or in the metabolic use of oxygen and glucose by the brain until the eigth decade of life; and even at 80-plus, the decreases noted in some individuals may relate to disease processes. However, these data do not take into account the complexity of brain function. Specific cells at particular times, for example, require the increased use of glucose. Thus measuring total blood flow and the use of oxygen and glucose may not reflect a reduced ability of particular cells to meet their immediate energy needs. Changes are dramatic in those suffering from a stroke : it is most common in the elderly. From middle age onward, there is a doubling in the frequency of stroke in each successive decade of life. > 50% of survicors have functional impairments, ranging from the inability to function in the work force to loss of ability to carry out activities of daily living (ADL). Stroke is estimated to account for 10-20% of all dementia cases
sensory functions :

skin sense : the number of Pacinian corpuscles and Meissner corpuscles decrease throughout life. Little change occurs with age in the number of Merkel disks and free nerve endings. There is a decrease in sensitivity to touch (particularly in the hand region) and in the ability to distinguish between 2 spatially distinct points of contact. High-frequency vibration is sensed less well with increasing age by the Pacinian corpuscles, particularly in the feet and legs.
proprioception : there is a decrease in the number of receptors in the vestibular apparatus compensated for by changes in the response of the CNS to vestibular apparatus stimulation. The elderly often experience light-headedness and vertigo due to altered functioning of the vestibular apapratus
hearing loss associated with senescence is called presbycusis and it affects almost 40% of those aged > 65. There is atrophy, as well as loss, of the hair cell that encode high-frequency sound, and thus hearing loss. There is also a loss of hearing due to a loss of nerve cells of the auditory nerve with advancing age. Hearing loss may result from a reduced blood supply to the cochlea, as well as alteration in the structure of the basilar membrane. Hearing loss due to changes in the external and middle ear appear to be of minor importance; although accumulation of wax in the external ear does cause hearing loss in many, that problem can be easily rectified by removing the wax. Long-term exposure to intense sounds, such as those from power tools or loud music, are contributors to presbyacusis. Some researchers feel that lifetime exposure, rather than intrinsic aging, is the cause of presbycusis. Many elderly have difficulty in distinguishing spoken words, a problem magnified by background noise, a likely contributor to an age-associated decline in cognitive ability
vision : resting pupil size decreases, thus reducing the illumination of the retina. The change in the physical properties of the lens and in the functioning of the ciliary muscles leads to a loss in power of accommodation (presbyopia ). The loss in acuity foes not appear to be due to the small loss of cones, but more likely results from a decrease in the number of neurons making up the optic nerve. The slight loss in rods that occurs with increasing age appears to be compensated for by hypertrophy of the remaining rods. Nevertheless, there is an impairment in rod vision in that the elderly have reduced ability to adapt to very low-intensity light. The reduced ability of the elderly to discriminate colors in the green-blue-violet region of the visible light spectrum does not appear to be due to a defect in the cones, but rather relates to a yellowing of the lens with increasing age, increasing susceptibility to glare. Over 50, there is generally some loss in depth perception, for reasons that remain to be identified. See also gerontotoxon / arcus cornea / gerontoxon , cataract , glaucoma , and age-related macular degeneration (ARMD)
taste and smell

motor functions :

motor responses to sensory input : reaction time has been found to be slowed at advancing ages. Although this is due, in small part, to the slowing of both muscle contraction and peripheral nerve impulse conduction velocity, it is primarily the result of the slowing of central processing. Reaction time in the elderly is slowed even more when the individual is confronted with a choice of alternative responses. The extent of this slowing increases as the movement increases in complexity : this reduced speed appears to enable the elderly to maintain accuracy of movement. The loss in ability to precisely control skeletal muscle activity is illustrated in handwriting, for example, or reaching for objects, interfering with daily living activities
posture and balance : elderly people have deficits in skin receptors, proprioceptos in the muscles, tendons and joints, receptors in the vestibular apparatus, and receptors in the visual system, and thus would be expected to have postural and balance problems. However, these many systems provide redundancy of information. Nevertheless, both the speed of central processing and muscular strength do decrease with increasing adult age, and these factors tend to adversely affect posture and balance. The sway difference between the old and the young becomes much more pronounced when the individual stands on only one foot : dynamic balance is shown to be compromised to varying extents in most of the elderly. Deterioration of posutre and balance is only one of many factors underlying the increasing incidence of falls with advancing adult age.
locomotion : it would be expected that the elderly would show changes in walkin because of the deterioration of the sense organs and joints and the loss in skeletal muscle strength. Surprisingly, there is only a modest change in walking in those who are free of discernible diseases, such as Parkinson's disease, strokes, cerebellar degeneration, and osteoarthritis. Walking in the healthy elderly is slower than that of the young : this slownes is often not because they are not able to walk faster, but rather that they prefer to walk slower. Walking speed decreases more rapidly with increasing age in women than in men. During fast walking the elderly take shorter, more frequent steps than the young. Endurance of limb muscles is enhanced by shorter strides, and the energy cost of walking is reduced. A shorter stride length is also less taxing when ankle and knee joints are less flexible. In addition, in taking more steps to cover the same distance, both feet are on the ground for a greater fraction of time; and this may be important for the elderly because of their more fragile balance.
age-associated motor disorders : Parkinson's disease and Huntington's disease
regular exercise keeps us fit. But not everyone is born equal: a few people get little benefit from physical activity because their genetic makeup doesn't allow it. Research now shows that the same holds true for the elderly, where the stakes are much higher. A third of adults over 70 in the US are unable to walk for 500 m without difficulty, or to climb up 10 steps without having to stop for a rest. Such people are 4 times more likely to end up in a nursing home, and 3 times likelier to die before those who are fitter. A 4-year study of 3,000 American adults in their 70s examined participants every 6 months, and asked them about their mobility and how much exercise they took. A third of the group reported that they were 'active', burning > 1,000 calories per week during exercise - the equivalent of walking for about 5-6 hours. And 40% of the study group developed some sort of mobility problem during the 4 years. There are 2 types of angiotensin-converting enzyme (ACE) gene, which is important in heart strength and regulating blood pressure : the slightly shorter one, called D for deletion, results in the synthesis of higher levels of the enzyme than its longer counterpart, I, or insertion. Studies have shown that among athletes, those with 2 copies of the 'D' form excel in sports that rely on strength and power. While those with 2 copies of the 'I' form tend to be better at endurance sports. Those with 2 'D' genes - about a third of the overall group - were most likely to retain their mobility. Perhaps they had extra strength that protected them from injury. At the other end of the scale, those with 2 copies of the 'I' gene were 45% more likely to develop difficulties than those with at least one 'D' gene, regardless of how much they exercised^ref. This doesn't mean that senior citizens with 2 'I' genes might as well become couch potatoes : those who exercised regularly were still less likely to develop mobility problems, regardless of their genetics. Even if those with 2 'I' genes can't benefit from exercise as much as their comrades with more favourable gene profiles, they are still better off for a brisk walk.

Web resources

NIH senior health exercises

autonomic nervous system : the concentration of norepinephrine in the blood increases with increasing age, and the increase in its concentration in response to stress is greater and lasts longer in the elderly. There is an increase in sympathetic nervous activiyy. At least in some organs, there is a reduced ability of target cells to respond to norepinephrine.
sleep : with increasing age, the most marked change in the EEG is the reduced voltage of the electrical potential during slow wave sleep (SWS). Also, the length of time of REM sleep is decreased, as are eye movements. In the elderly, sleep is fragmented with frequent awakenings. A major reason for the awakening is an age-associated increase in sleep apnea . In older men, sleep is also interrupted because of urinary urgency that is secondary to benign prostatic hypertrophy . > 33% of people aged > 60 complain of sleep disturbances.
cognitive functions :

attention : the ability to focus on and perform a simple task does not undergo an appreciable age-associated change. Brain stem and thalamus remain functionally intact. However, in the presence of distractions, the ederly are less able to focus on a task than are the young.
memory : sensory-perceptual memory does not appear to be a major reason for memory deterioration with increasing adult age. There appear to be little, if any, change in primary memory with increasing adult age. Working memory has been found to deteriorate at advancing age. The elderly have greater problems with episodic memory than do younger people. Semantic memory is well retained in the healthy elderly, although it may take longer to retrieve this information than is the case in younger people. Procedural memory does not deteriorate with age.
intellectual functions : intellectual performance changes little in the absence of disease during adult life. However, times tasks show marked deterioration at advanced ages. Although old people can learn, the speed of learning decreases with advancing ages. Some elderly individuals maintain a high level of creativity in the tenth decade of life (e.g. Pablo Picasso, Pablo Casals, and Frank Lloyd Wright) and some even develop creativity at that age (e.g. Mary Robertoson "Grandma" Moses), but creativity is of difficult definition.
age-associated cognitive disorders : dementia and Alzheimer's disease

cardiovascular system :

heart : in healthy people, there is a modest increase in the size of the heart from ages 20 to 80 primarily due to hypertrophy of cardiomyocytes leading to an increase in thickness of the wall of the left ventricle. This increase is far greater in people who suffer from systemic arterial hypertension .

conductile system : after age 60 there is a progressive decrease in the number of cells in the SA node. There is also some decrease in the resting heart rate with increasing adult age, and this appears to be due, in part, to a change in the SA node's pacemaker function. There is also some change with age in the AV node and its connection to the conductile system in the ventricles, causing a minor delay in the progression of action potentials from the atria to the ventricles. Increasingly common with increasing age are arrhythmias : sudden death due to arrhythmia may be relatively old in the very old.
pump function : with aging, there is a slowing of the flow of blood into the left ventricle during early diastole, but this is compensated for by the increased amount of blood pumped by left atrial contraction in late left ventricular diastole. Thus, at rest, the total amount of blood entering the left ventricle during diastole is similar for old and young people of the same size and gender. The stroke volume in resting healthy people is similar for the old and young of the same size and gender, as is the cardiac output. The contraction of left ventricular muscle cells is prolonged with increasing age, and this prolongation helps the healthy old maintain a stroke volume similar to that of the young. Substantial differences emerge when a person is challenged
neural regulation : the influence of the sympathetic nervous system is blunted with increasing age. In healthy old people, there is much less increase in heart rate and ventricular contractility in response to exercise. Instead, there is an increase in the blood volume in the chamber of the left ventricle at the end of diastole, causing an increase in the length of the left ventricular muscle cells. Within limits, an increase in the length of cardiac muscle cells increases the force of their contraction. The elderly uses the Frank-Starling mechanism rather than orthosympathetic regulation : thereof in the elderly there is an increase in stroke volume during exercise that is secondary to the increased diastolic volume of the left ventricle. In the elderly who suffer from age-associated cardiovascular disorders, this compensatory ability is compromised
coronary heart disease
congestive heart failure

arteries :

arterial structure : with increasing age, there is an increase in the diameter of thelumen of the large arteries. The walls of these arteries increase in thickness, and they also become stiffer. While there is less increase in the lumen diameter of the smaller peripheral arteries, there is greater increase in their wall thickness. These changes are due to a decrease in the elastin/collagen ratio, increased mineralization of the elastin with clacium and phosphorus; and an increase in sustained contractile activity of smooth muscle in the walls of the arteries. There is increased velocity of the pulse wave, which stems from the increased stiffness of the arterial walls. Arterial impedance refers to the opposition to the ejection of blood into the aorta from the left ventricle. An increase in the diameter of the lumen of the large arteries decreases impedance, while an increase in stiffness in arterial wall increases it. Through middle age, these 2 factors are in balance and impedance does not change appreciably, but at advanced ages the increase in stiffness prevails and impedance increases. With increasing age, atherosclerosis progressively alters the structure of arteries in many, but not all, people.
blood pressure : systolic, diastolic and mean arterial pressure increase between the ages of 20 and 70. The increase in mean and diastolic blood pressure is primarily due to an increase in the resistance of arterioles. The increase in systolic pressure stems from the increased stiffness of the walls of the large arteries as well as to increased resistance of the arterioles. However, not all populations show age-associated increase in blood pressure. Systemic arterial hypertension occurs in over 60% of the elderly. About 30% of the population over 65 show a blunting of the arterial baroreceptor reflex leading to orthostatic systemic arterial hypotension , a contributor to falls by the elderly. The elderly are also prone to postprandial hypotension due to an inability to compensate for the decrease in the resistance of the arterioles of the gastrointestinal tract by increasing the resistance of arterioles of other regions.

microvasculature :

resistance vessels : in many people, there is an age-associated increase in resistance to blood flow because the arterioles are too constricted, and this appears to be a major reason arterial blood pressure tend to increase with age. The regulation of the size of the lumen of the arterioles by the autonomic nervous system is no longer fully effective in redistributing blood flow.
exchange vessels : no change with age in structure and function. However, in some tissues, the number of capillaries decreases at advanced ages
venous system : all veins are thin-walled compared to the arteries, and contain smooth muscle that is controlled by the sympathetic nervous system. With increasing age, there is a reduction in the distensibility of the veins and in the strength and speed of smooth muscle function. There may also be some loss in the efficiency of the sympathetic nervous system control of the smooth muscle of the veins. In addition, there is an age-associated widening of the veins; this interferes with the proper functioning of the valves and, as a result, there tends to be a collection of fluid in the legs.

respiratory system : with aging there is a decrease in the elastic forces of the lungs tending to reduce the volume of air in the lungs and the elastic forces of the thoracic wall and diaphragm tending to increase it, though the decrease in the force is much greater for the lungs. As a result, the FRC increases with increasing age; this is the reason that elderly people tend to develop what is called a barrel chest. The vital capacity decreases with increasing age, because of the changes in the physical properties of the thorax-lung system and the diminished force-generating ability of the respiratory muscles. The residual volume (the amount of air remaining in the lungs after a maximal forced expiration) increases with advancing age for the same reasons. There is a progressive decrease in the FEV₁ after age 25, because of the increased resistance to air flow in the bronchioles, the change in elastic properties of the lungs, and the decrease in the force generated by the respiratory muscles. The decline in FEV₁is about 30 ml per year for nonsmokers, and it is greater than that for smokers. The unevenness in alveolar ventilation increases with increasing age. In spite of the age changes in the lung-thorax pump, alveolar ventilation in the healthy elderly is not sufficiently altered to limit their ability to carry out vigorous exercise. However, such is not the case for those suffering from chronic obstuctive pulmonary disease occurring in a subset of smokers. The age-associated decrease in the surface area of the alveoli and the increase in the unevenness of alveolar entilation decrease the concentration of dissolved oxygen in arterial blood with age at the rate of about 4% per decade after age 20. Fortunately, this decrease has little effect on the amount of the oxygen carried to the tissues because hemoglobin is almost fully loadedwith oxygen. However, a further decrease in dissolved oxygen can cause problems, and thus the elderly are more vulnerable to pulmonary diseases, such as pneumonia. Anemia does not occur in the healthy elderly, but is a frequent result of age-associated diseases. There is no poblem with the transport of CO₂ to the alveoli from the cells : COPD patients may accumulate CO₂ in their body fluids as a result of inadequate alveolar ventilation, rather than a transport problem
renal and urinary system : starting in young adulthood, the mass of the kidneys decreases progressively with increasing age. This loss in mass occurs primarily in the cortex of the kidney, with little loss occurring in the medulla. Kidney blood flow decreases with increasing age, with a decrease > 50% between the fourth and ninth decades of life. Much of the decrease stems from the constriction of kidney arterioles. About 20% of the blood plasma flowing to the kidneys is filtered across the walls of the glomerular capillaries into the lumen of the nephrons. The GFR shows a decrease with increasing age, with those in the age range of 75 to 84 having about 70% of those in the age range of 25 to 34, but not all exhibit a decreased rate. It may be due to some disease process, such as hypertension or the long-term effects of an infectious disease experienced earlier in life. A few elderlies have age-associated diseases that cause such a marked reduction in GFR that dialysis or a kidney transplant is required. Most of the tubular transport system continue to function effectively with advancing age. Alteration in the RAS is probably the main reason that the kidneys of the old have a reduced ability to conserve sodium when challenged by a diet low in sodium. Moreover, the lower blood levels of aldosterone may also explain why the elderly tend to have high plasma levels of potassium. With increasing age, the kidneys are also less able to increase the excretion of sodium in the urine to meet the challenge of a high dietary intake of sodium due to a decrease in both renal blood flow and glomerular filtration. The elderly respond to an increase in body fluid solute concentration by secreting more vasopressin than do the young. However, the kidneys of the old do not increase water reabsorption in response to vasopressin as effectively as do the young : there is a progressive loss in the ability to excrete a scant, highly concentrated urine, exacerbated by the fact that the elderly have a blunted thirst response when suffering water deprivation, making it less likely that they will seek the drinking water. The ability of the kidneys to excrete a high volume of dilute urine in response to a high intake of water decreases with increasing age. Fortunately, this physiological deficit rarely causes serious problems for the elderly unless there is a coexisting disease. Hydrogen ion concentration in the blood increases progressively with increasing age in most healthy people; on average, it is 6-7% higher in 80-year-olds than in 20-year-olds : since hydrogen ions can dissolve bones, this could be a factor in the age-associated loss of bone mass. The reduced ability of the kidneys to excrete hydrogen ions both predisposes the elderly to metabolic acidosis and delays their ability to recover from it. There is a decrease in the ability to postpone voiding. 15-30% of the community-dwelling elderly suffer from urinary incontinence
gastrointestinal system

motor activity :

mastication : in the absence of dental interventions, it is often greatly compromised with increasing age. Also the skeletal muscle involved in mastication become weaker
swallowing : in the healthy elderly, any changes in the swallowing process that occur do not cause significant functional difficulties. Age-associated diseases such as stroke , Parkinson's disease , ALS , and myasthenia gravis , as well as achalasia and reduced compliance of the upper esophageal sphincter (more common in the elderly) may adversely affect motor nerve control of the process. Heartburn increases with age
gastric and intestinal motility : gastric emptying is slowed with advancing age only when a meal is very large. Motor activity of the small intestine appears to change little with advancing age
colon motility and defecation : in healthy people there is no change in the motor functions of the colon with advancing age. The elderly frequently complain of constipation , but it does not occur more frequently in the elderly than in the young. The healthy elderly do no suffer from diarrhea. Fecal incontinence can be a problem for the elderly because of higher rectal pressure and reduced force of the anal sphincters.

secretion : while there is disagreement as to whether the secretion of saliva decreases with increasing age in healthy people, there is agreement that medications used to treat age-associated diseases do cause alterations in salivary secretion. Atrophic gastritis increases in prevalence and severity with increasing age. This inflammatory disease, probably caused by an autoimmune mechanism, leads to destruction of the parietal cells which secrete hydrochloric acid, so that elderly will not be able to effectively absorb vitamin B₁₂ (pernicious anemia ). Although some changes in the secretion of pancreatic juice have been found in studies with healthy elderly, such changes are not great enough to affect the physiological functions of this secretion. The major effect of aging on the biliary system is the increased likelihood of gallstones due to the change in the composition of the bile with increasing age, particularly the increase in cholesterol concentration, and the reduced contractile response of the gallbladder to CCK
digestion : there appear to be no deterioration with age in the ability to digest starch. There is no age-associated problem in the digestion of sucrose. In those susceptible to lactase deficiency, there is decreased ability to digest lactorse with increasing age (referred to as lactose intolerance), but those not afflicted with this genetic characteristic show no age-associated difficulties in digesting lactose. The healthy elderly have little difficulty in digesting protein and fat. However, studies have shown that the elderly do not handle masive intakes of either substance as well as do the young.
absorption : the capacity of the intestine to absorb glucose show an age associated decrease. However, the capacity to absorb glucose is so much greater than needed when eating any of a wide range of usual diets that this change does not pose a problem for the healthy elderly. This also appears to be true in regard to the absorption of the products of protein and fat digestion. The ability to absorb calcium deteriorates at advanced ages. There tends to be an age-associated decrease in both the amount of available vitamin D and in the ability of the kidneys to convert it to the needed hormone. Also with increasing age, there is a blunting of the action of this hormone on the calcium absorption system of the small intestine.

endocrine ad metabolic function^ref

energy metabolism : total daily energy expenditure (ie., daily metabolic rate) decreases with increasing adult age.It seems likely that the major reason for the decreased BMR is the change in body composition with age, namely the decreasing skeletal muscle mass and the increasing adipose tissue mass, the latter having a much lower metabolic rate than most other tissues. The contribution of physical activity ranges from an estimated 15 to 30% of the total daily energy expenditure : it is believed to decrease significatively, based on extensive evidence that physical activity decreases with age.
carbohydrate and fat metabolism : older people usually show higher plasma glucose levels during OGTT than do young people; i.e, they have less ability to utilize glucose (IGT). There is an age-associated decrease in the response of many cells of the body to insulin (increased insulin resistance). The major causal factor appear to be the decrease in physical activity and the increase in adipose tissue mass. Indeed, there is little increase in insulin resistance in the elderly who are physically fit and relatively lean. There is an age-associated increase in the plasma concentration of LDL in most men until about age 50, and in women until about age 70. Women have an age-associated increase in plasma HDL concentratiomn until about age 60, while men have lower levels of HDL than women throughout adult life; however, men show an increase in HDL from age 50 to 65, which narrows the gender difference. Those who are physically fit and have only a small increase in body fat do not undergo the age changes in plasma lipoproteins that increase the risk of atherosclerotic disease nor, as stated above, do they exhibit an appreciable increase in insulin resistance. Type II diabetes, which has many of the characteristics of syndrome X but in an exaggerated form, increases in prevalence with increasing age. It is estimaated that 20% of individuals in the age range 65 to 74 suffer from type II diabete. It is logical to think that this type of diabetes is an outgrowth of syndrome X. In addition to a marked insulin resistance, there is also an impaired ability of the pancreas to secrete insulin in those with type II diabetes.
protein metabolism : there is a decrease in the rate of protein synthesis and protein degradation. As they reside in the body, protein molecules are gradually damaged by oxidation, glycation, heat, and other factors. The age-associated decreased secretion of GH may decrease the use of fat relative to protein and decrease protein synthesis => decrease in muscle mass and increase in body fat
stress : with increasing age, there is increased systemic activity of the sympathetic nervous-adrena medullary system in response to stress. However, at least at some target sites, the response of the cells to this system is blunted with increasing age (e.g. the response of the heart). Under conditions of stress, plasma cortisol levels increase more in the elderly than in the young, and the increase is more prolonged. However, whether this increased cortisol response is beneficial or detrimental remains to be determined
Although the secretion of growth hormone falls by about 12% per decade after middle age, perhaps the greatest attention has focused on sex steroids, since estrogen secretion falls abruptly in postmenopausal women, and testosterone levels decline with age, though more gradually, in men^ref1,
ref2. Levels of the adrenal sex steroid dehydroepiandrosterone (DHEA) and its sulfate ester fall progressively after 30 years of age, and after 60 years of age are less than half the levels in youth^ref. there is a marked decrease in DHEA and melatonin with advancing age. The blood level of DHEA peaks at about age 20 and decreases thereafter, so by age 60 the level is 60 to 70% of that at age 20. Low levels of blood DHEA have been associated with some forms of cancer, cardiovascular disease, dementia, diabetes, obesity, and osteoporosis. Melatonin is believed to serve in inducing sleep, and the low levels associated with aging could be a factor in insomnia and the elderly

^ref

reproductive system : compared with people younger than 60 years, sexual activity is regarded as less important. This is mainly explained by the elderly with body complaints. Men wish more sexual activity than women, but experience more body complaints than women. Women more often than men have no partner for sexual activity.

female reproductive system : in studying the infleunce of age on fertility, what is usually measured is the number of live births per thousand women in a particular age range. However, because of confounding factors such as contraception and abortion, this measurement may bot be an accurate index. Communities of Hutterites (a religious sect that originated in Moravia and now living in Canada and the northwestern USA), whose beliefs prohibit contraception and abortion, provide a population in which some of the confounding factors are circumvented, indicating a drop in fertility at ages 35 and greater. This conclusion is strengthened by studies of women in programs of artificial insemination, where the fertility of the male partner and the frequency of coitus are not confounding variables. The fact that women over age 50 rarely give birth provides clear evidence that there is an almost complete loss of fertility by that age. At ages over 30, there is an increase n spontaneous abortions, and about 50% of the aborted embryos and fetuses show genetic abnormalities. Moreover, with increasing age of the mother, starting at about 30, there is a progressive increase in the number of newborns with chromosomal abnormalities. Menopause is believed to result primarily from the ovary's loss of ability to secrete estradiol, while plasma FSH and LH levels rise markedly due to the lack of negative feedback. Pubic hair decreases and the vagina shortens, loses elasticity, and is at increased risk of bacterial infections and mechanical damage. The oviducts shorten, and their diameter decreases. There is atrophy of the glandular structure of the breast, with replacement by adipose tissue. The uterus reduces in size, and there is atrophy of the cervix. The incidence of breast cancer increases with advancing age. While cancer of the uterine cervix does occur in elderly women, it peaks from ages 48 to 55. Peak age range for cancer of the uterine endometrium is 60 to 64
male reproductive system : there is atrophy of the seminiferous tubules with advancing age. In men over 80 only 10% of the tubules contain sperm. Nevertheless, some sperm are found in the ejaculate of about half the men in the age range of 80 to 90. Indeed, there is evidence that at least some men are still fertile at 80-plus years. The mean reduction in plasma free testosterone is about 30% between the ages of 40 and 70, but some older men have levels well within the range found in young men. The secretory activities of the seminal vesicles and the prostate decrease with increasing age, and thus the ability to produce semen is diminished. The force of release of the semen from the penis is markedly reduced, as is the volume released. Benign prostatic hypertrophy affect 90% of men by age 80. Prostate cancer is rare before age 50, but is a common form of cancer with further increasing age. Although in many men it progresses slowly (particularly at advanced age), it is the third most common cause of death in men over 55. Sexual impotence increases with increasing age : 50% are affected in the ninth decade.

immune system : see immunology and aging
thermoregulation : with increasing age there is a deterioration in the ability to regulate body temperature and, thus, to meet the challenge of different thermal environments. It must be noted that the extent of this deterioration varies among individuals, depending on health, physical fitness, and lifestyle factors, such as alcohol consumption and smoking. In a hot environment, the elderly have a reduced ability to redistribute blood flow from the core of the body to the skin, due to structural changes in the skin blood vessels and to decreased capacity to constrict the vessels supplying the viscera. In addition, the sweating response is decreased with increasing age. In a cold environment, the elderly show a decrease in constriction of skin blood vessels and a reduced shivering ability. Elderly people have a much greater risk of developing heat stroke (hypothermia with rectal temperature > 106°F) and hypothermia (a rectal temperature < 95°C) than do young people. One reason for this greater risk is the deterioration of the physiological processes involved in maintaining body temperature. However, the main reason the elderly are more vulnerable to extremes in environmental temperature is the blunting of their perception of ambient temperature. This loss is critical, because humans utilize behavioral responses rather than physiological responses as their major mode of coping with temperature extremes.

A fingerprint of gene activity could reveal the true 'youthfulness' of our kidneys, hearts and muscle, regardless of our biological age. The technique might one day be used to find healthy organs for transplants or to warn us of impending disease. It's hard to tell, particularly on a cellular level, whether a young and healthy body conceals a withering heart — or conversely, whether an old man has a vigorous ticker like that of a younger man. Activity of a set of genes reveals how well organs are operating, regardless of their owner's actual age. The team analysed the activity of thousands of genes in 81 muscle samples from people aged between 16 and 89. They pulled out a set of 250 genes whose activity goes markedly up or down with age. When they compared the activity of these genes with the muscle fitness of individuals, measured by the size of their muscle fibers, they found that the genetic profile, rather than a person's age in years, was a more accurate indicator of fitness. The speed with which our cells and bodies deteriorate is determined partly by the genes we inherit from our parents and partly by the ravages of living. These factors can change the rate at which certain genes manufacture proteins, and other aspects of the cell's machinery. Some studies, for example, have shown that telomeres decay over time and do so faster in those who indulge in unhealthy activities such as smoking. One 64-year-old man had a pattern of gene activity more like that of a younger person : indeed, under the microscope, his muscle appeared young; it contained bigger 'fast twitch' fibers that are good for sprinting and more prevalent in young muscle^ref. In an earlier study, the same group detected a 78-year-old woman with a kidney more like that of a centenarian, according to her genetic profile and an inspection of the tissue under the microscope^ref. The researchers found that aging affects some of the same genes across many different tissue types and in many different animals. One group of genes, which is involved in generating energy in the cell's mitochondria, quiet down with age in human muscle, kidney and brain tissue, and also in aging mice and flies, even though these animals have very different lifespans. It may be that this pathway is a weak spot in the cell that is particularly vulnerable to aging. Such techniques could one day be used to identify donor organs that are normally ruled out because of the donor's age but may actually be in good working order. In future, a routine blood test at the doctor's office could also reveal the true working condition of organs, allowing patients to modify their lifestyle or diet to rejuvenate their bodies. But to do this researchers will need to find a way to gauge the activity of an organ's genes from molecules in the blood rather than from a tissue sample, which is difficult to obtain
Prevention : possible interventions to retard aging^ref

dietary restriction : reducing food intake, starting soon after weaning, increases the length of life in rats. Antiaging action of dietary restriction (DR) is challenged by the fact that because DR was initiated soon after weaning in the early studies, many felt that its antiaging effects were due to a retardation of growth and development. It is almost as effective when initiated in the young adult rat and mouse. Indeed, DR even shows a significant, though less marked, antiaging action when initiated in rodents entering middle age. In addition to increasing the length of life, DR also slows the age-associated deterioration of most physiologicial processes in rats and mice. DR also delays the age of onset and/or the rate of progression of most age associated diseases in genetic strains of mice and rats that are predisposed to those particular age-associated diseases (cancers, kidney diseases, and autoimmune diseases). An obvious question was whether the antiaging actions of DR were due to the reduced intake of a specific dietary component, such as fat or possibly a mineral or a specific vitamin. It is not the restriction of a particular food substance that is significant, but rather the restriction of energy (calorie) intake : hence DR should be renamed caloric restriction (CR). The absolute amount and the percent fat content of rats and mice are decreased by DR. Reduction in body fat content is not causally related to DR's ability to increase length of life. Another widely held view was that DR retards senescence by decreasing the metabolic rate. While the metabolic rate of rats per gram of lean body mass has been found to decrease upon initiation of DR, the decrease is transient; and within 2 weeks, there is no difference in metabolic rate between rats on restricted food intake and those eating ad libitum. Indeed, there is evidence that DR alters some of the characteristics of fuel use (other than metabolic rate) : plasma glucose level of the DR rats is about 15% below that of the ad libitum fed rats. Moreover, DR causes about a 50% decrease in plasma glucose levels. DR does not cause a decrease in the rate of glucose use as fuel per gram of lean body mass. Thus the ability of DR to enable effective carbohydrate fuel use at reduced levels of plasma glucose and insulin may well play an important role in its antiaging action in rodents. In addition, DR in rodents decreases the age-associated increase in oxidative damage : DR protects the rodent by decreasing the generation o ROS and increasing the ability to detoxify such molecules. DR increases the expression of heat shock proteins and leads to elevated daily peak plasma concentrations of glucocorticoids : both of these actions may well increase the ability of the organism to cope with stressors. From a practical point of view, few people would be likely to adhere to such intensive dietary restriction over an extended period involving much of the life span. Moreover, such a marked reduction in food intake poses the threat of malnutrition because of possible deficiencies in essential nutrients, which is not a problem in laboratory rodents fed a scientifically designed diet.^ref1,
ref2
pharmacological interventions :

antioxidants : vitamin E , butylated hydroxytoluene (BHT), vitamin C , methionine, b-carotene, menadione-sodium-bisulfite, and selenite are much less effective than DR in retarding senescence in these rodent models; they only modestly increase, if at all, the mean length of life of rodent populations, and do not increas the maximum life span of the populations. Nevertheless, antioxidant preparations are being sold for use in pharmacological doses to retard human aging. Indeed, there is epidemiological evidence that indicates that some antioxidants may retard some aspects of human aging. For example, vitamin E in pharmacological doses has been found to lower the incidence of coronary heart disease and to enhance the immune system in elderly people. Supplementation of the diet with selenium has been reported to decrease the incidence of lung, prostatic and colorectal cancers. Although inadequate dietary intake of vitamin C increases the risk of cataracts, cancer and coronary heart disease, there is no evidence that megadoses of vitamin C afford further protection from these age-associated diseases. While it has been reported that b-carotene retards age-associated cardiovascular disease and cancer as well as helping to maintain memory, the validity of these claims is the subject of controversy.
GH : when subjects were injected with human GH for 6 months, and they havd a 9% increase in lean body mass, a 14% decrease in fat mass, a 1.6% increase in lumbar vertebral bone density, and a 7% increase in skin thickness. However, some of these positive effects tended to disappear when the study was extended for another 6 months. It did not improve muscle strength, endurance, or mental ability and require further study. There are concerns about potential negative effects, such as the development of diabetes, hypertension, and carpal tunnel syndrome. GH must be prescribed by a physician, given by injection (it is a protein destroyed by digestive processes if taken orally), and is expensive (about $15,000 per year)^ref
DHEA retards the age-associated occurrence of diabetes and cancers as well as memory loss in rodents and autoimmune-related mortality in autoimmune-prone mice. However, DHEA administration also decreases food intake by rodents, and there has been much debate as to whether DHEA directly retards aging in rodents or does so by causing DR. DHEA improves immmune function, increase plasma IGF levels, and improve physical and psychological well-being. High doses of DHEA can cause liver damage. Also DHEA can be converted in the body to both estrogen and testosteronem, and the extent of these conversions is unpredictable; excess estrogen is a risk factor for breast cancer, and excess testosterone may promote prostatic cancer in men and produce a masculinizing effect in women. Recent years have seen a series of high-quality randomized, placebo-controlled trials lasting 6 months to 2 years that have assessed the efficacy of DHEA in older adults. A study by Nair et al. showed no effect of the administration of DHEA for 2 years (at a dose of 75 mg per day in men and 50 mg per day in women) on body composition, physical performance, or insulin sensitivity, as compared with placebo. Among patients with baseline sulfated DHEA levels that were less than the 15th percentile for normal young women and men — a median value of approximately 0.4 µg/ml (1.1 µM) in women and 0.7 µg/ml (1.9 µM) in men — the levels increased in both sexes by about 3.5 µg/ml (9.5 µM) after treatment with DHEA^ref. The results are largely confirmatory. The French DHEAge study, reported in 2000^ref, evaluated DHEA (at a dose of 50 mg per day), as compared with placebo, in 280 healthy subjects between the ages of 60 and 79 years. The beneficial effects of treatment were restricted to women and were limited to an increase in libido without improvement in either body composition or muscle strength^ref. Muscle power and frailty were specifically addressed in a recent study by Muller et al.^ref, which detected no differences between the DHEA group and the placebo group. Reductions in fat-free mass and insulin levels were observed in a 6-month intervention study, but the number of subjects who were studied was small^ref. Positive changes in BMD have been repeatedly observed, but these changes have been small, specific to site and sex, and not reproducible between studies. The DHEAge study demonstrated improvements only in women; these increases in BMD occurred at Ward's triangle in women who were under the age of 70 years and at the radius in those over 70 years^ref. The study by Nair et al. showed a slight increase in BMD in the femur in men and in the radius in women. Jankowski et al. reported similar skeletal results after 12 months of therapy in 69 elderly men and women, with a 1.2 to 1.6% increase in BMD at the hip, as compared with that in 71 placebo-treated controls^ref. Overall, these inconsistent changes in BMD are approximately half those observed with current osteoporosis therapies, such as estrogen and bisphosphonates, and are unlikely to have a significant effect on the risk of fracture. The study by Nair et al. showed that the quality of life of the subjects was unchanged after the administration of DHEA, although, on the basis of the standard deviations in scores on the mental and physical components of the Health Status Questionnaire used in the study, it is likely that the study was not adequately powered to detect clinically meaningful differences in this measure. In a parallel component of the overall study, elderly men with total testosterone values below the 15th percentile in a normal young cohort were given transdermal testosterone sufficient to raise their testosterone levels from a median value of 357 ng/dl (12 nmol/l) at baseline to 461 ng/dl (16 nmol/l). Again, no significant functional changes in any of these measures were observed, and increasing evidence suggests that physiologic testosterone replacement should not be given to otherwise normal aging men^ref. In the context of a prescribed medication that falls within the guidelines of health care providers and pharmaceutical regulatory networks in most countries, this evidence will be subjected to professional peer review. However, another "negative" study on the efficacy of DHEA is unlikely to have much effect on its use in Western societies. Owing to a loophole in U.S. legislation, DHEA is regarded not as a drug but, rather, as a dietary supplement. Although DHEA was never approved as a drug by the FDA, its status changed from drug to food supplement under the Dietary Supplement Health and Education Act of 1994. Companies that sell supplements may not claim that the products prevent, treat, cure, mitigate, or diagnose disease, but these guidelines are often ignored or circumvented, as appears to be the case with many current providers of DHEA. A search of the keyword "DHEA" on the Internet is most revealing — > 5 million hits on Google, with many online vendors extolling DHEA as the "foundation of youth," with erroneous and misleading claims. The FDA does occasionally act when supplements are marketed as drugs^ref, but, in reality, the FDA has had little impact on this situation. Without a reversal of the current U.S. legislation, DHEA is likely to continue to be used inappropriately, and quackery will prevail. Furthermore, the FDA has no requirements for the composition of supplements. As a result, commercially available DHEA preparations contain from 0 to 150% of the amount stated on the package^ref. Although DHEA and sulfated DHEA are the most abundant steroids secreted from the adrenal cortex, when compared with their corticosteroid counterparts — cortisol and aldosterone — they remain something of an enigma. DHEA is not essential for life (indeed, rodent adrenals do not make DHEA), and the involvement of tissue-specific receptors or intracellular signaling pathways is unclear. Many of the actions of DHEA are thought to be mediated by downstream metabolism within target tissues (such as brain, bone, adipose, and skin) to androgens and estrogens. However, the importance of these pathways is undefined, particularly in men, who have an overwhelming excess of circulating androgens anyway. There is some evidence for the therapeutic use of DHEA in patients with primary or secondary adrenal insufficiency^ref, though most studies of this group have focused on improvements in the quality of life. Further research focusing on the action of DHEA and its role in patients with DHEA deficiency is certainly indicated. Establishing the hormone's safety or lack thereof might lead to the reclassification of DHEA as a drug, since supplements are defined as causing no harm. To date, the DHEA trials involving elderly patients have shown neither meaningful benefits nor adverse events. Concern has been expressed about the downstream metabolism of DHEA to more potent androgenic metabolites within prostate or mammary glands, but no deleterious changes in prostate-specific antigen or prostate volume have been observed^ref1,
ref2. However, the report on the Women's Health Initiative study of estrogen replacement in postmenopausal women is a telling reminder that reversing an age-related endocrine deficit may actually cause more harm than good,^ref12 and ongoing vigilance is needed in cohorts of patients with adrenal insufficiency who are prescribed DHEA. The search for eternal youth will continue, but the reversal of age-related decreases in the secretion of DHEA and testosterone through "physiologic" replacement regimens offers no answer and should not be attempted. In light of an evidence base for the efficacy of DHEA in patients with adrenal insufficiency, DHEA should no longer be accepted as a food supplement and should instead be treated as a regulated drug. Appropriate regulation would dispel much of the quackery associated with this elusive hormone.
testosterone increases lean body mass, but has possible negative effects on the prostate, such as promoting the growth of those prostatic cancersthat are so slow-growing they would not cause a problem in the absence of this intervention. In a a 2-year, placebo-controlled, randomized, double-blind study involving 87 elderly men with low levels of the sulfated form of DHEA and bioavailable testosterone and 57 elderly women with low levels of sulfated DHEA, neither DHEA nor low-dose testosterone replacement in elderly people has physiologically relevant beneficial effects on body composition, physical performance, insulin sensitivity, or quality of life^ref
postmenopausal hormone therapy : estrogen retards postmenopausal bone loss. In this way, it reduces the rate of bone fractures due to osteoporosis. It blunts the age-associated progressive increase in coronary heart disease during the postmenopausal period of life. However, a recent clinical trial does not provide support for those studies. There is bias in subject selection : was the absence of protectie effect noted in the clinical trial due to the use of a progesterone analogue in addition to estrogen ? Estrogen therapy may improve memory. It increases the risk of uterine endometrial cancer. This risk can be eliminated if, in addition to estrogen, progesterone or a synthetic analogue of progesterone is given for 10 or more days per month. However, this combined hormone therapy results in monthly 3-to-4 day periods of vaginal discharge of blood and endometrial debris. ERT also increases the risk of breast cancer, and it is not clear that the combined estrogen-progestin therapy reduces the risk. In addition, estrogen therapy increases the risk of blood clots in the veins and gallbladder disease in women, while it produces unwanted feminizing effect in men^ref
deprenyl extends the lenght of life of old rats, mice, and hamsters, but the magnitude of this action was much less marked in Canadian and Japanese than in the 1988 Hungarian study. It has been suggested that the anti-aging action of deprenyl may not be due to its ability to inihibit MAO-B, but rather to its ability to function as an antioxidant : it increases the activity of the enzymes that protect the rat from oxidative damage^ref
melatonin is an antioxidant not well studied in humans : the possible long-term adverse effects of high plasma levels have yet to be properly evaluated^ref
when worm food was doped with 19 prescription medicines, from steroids to diuretics to anti-inflammatory drugs, most of the drugs had no effect, or even killed the worms at high doses. But anticonvulsant drugs (trimethadione, and 3,3-diethyl-2-pyrrolidinone) used to fight epilepsy increase mean and maximum life-span by as much as 50% of Caenorhabditis elegans and delay age-related declines of physiological processes. There is no proof that these drugs will extend lifespan in people, but the genes and molecules that control the ageing process in worms generally exist in mammals too. The anticonvulsant drugs appear to work without the help of these genes, because they prolong lifespan even when those genes are crippled. The drugs are known to act on the nervous system, but they were developed in the 1950s and their exact mode of action has never been worked out, but the drugs prompted the worms' nerves to trigger egg laying and movement. These compounds also regulated neuromuscular activity in nematodes. The nervous system somehow influences the rate of ageing in the rest of the body. Testing the drugs in humans remains difficult. Because the drugs are prescribed mainly to children, there is no suitable human group already taking them that could be studied. If their anti-ageing effects were to be tested in people, doctors would probably have to examine their effect on diseases associated with ageing such as diabetes or Alzheimer's, as it would take many decades for any effects on lifespan to show up^ref

lifestyle and environmental factors :

exercise : the physically fit have less risk of mortality during the next year than someone of the same age and gender who is sedentary. Moderate exercise, such as walking, is nearly as effective in reducing the risk of mortality as vigorous exercise, such as running the marathon, provided that the moderate exercise program is a sustained one (ie daily or several times a week year after year). Both aerobic exercise and resistance training benefit the elderly. It reduces the likelihood of developing hypertension and decreases the blood pressure of those suffering from hypertension; reduces the extent of abdominal obesity (potbelly); and increases blood levels of HDL, so reducing the risk of CHD and stroke. Exercise also decreases the occurrence of syndrome X and type 2 DM. It is surprising it has not been embraced by more of the people seeking the "fountain of youth". Jogging can cause joint damage; however, walking, which has benefits similar to jogging, rarely causes joint damage. Some forms of exercise can exacerbate osteoarthritis
diet : by decreasing the intake of calories, overweight people experience beneficial effects, including lowering the blood levels of glucose, lipids, and insulin as well as reducing blood pressure. Caloric reduction increases plasma HDL levels, decreasing rhe risk of CHD and stroke. Decreasing dietary fat intake is also beneficial by decreasing the intake of calories, decreasing plasma LDL levels, and preventing the occurrence of CRC and prostatic cancer. Those complex carbohydrates that contain soluble fiber help ward off aging problems; they reduce the formation of colonic diverticuli and decrease blood glucose and blood lipid levels. Fruit, peas, beans, and lentils contain goodly amounts of these carbohydrates. An increase in dietary protein may benefit many of the elderly, particularly those suffering from an infection or recovering from surgery. Meat, fish, poultry, eggs, and dairy products. Of course, high protein intake is not advisable for those with kidney disease. The dietary intake of calcium tends to be less than what is necessary to minimize age-associated bone loss (abut 1,200 mg of calcium per day, while most elderly consume only about 700-800 mg). Although diet is one source of vitamin D, much of it is generated by the action of sunlight on the skin. Since many elderly have only limited exposure to the sun, it would be helpful for them to adopt a diet that provides ample amounts of both calcium and vitamin D. Milk fortified with vitamin D is an excellent source of both, provided, of course, that the invidividual has no problem with lactose intolerance : in that case pill supplementation is available. In those elderly suffering from atrophic gastritis, vitamin B₁₂ deficiency could lead to pernicious anemia and neurological disorders, prevented by a daily dietary supplement of about 1 mg of vitamin B₁₂. Folic acid because a deficiency causes high plasma levels of homocysteine, a risk factor for CHD and stroke. Leafy vegetables, fruit, liver, and yeast are good sources of folic acid.
smoking is a risk factor for lung cancer, colorectal cancer, cervical cancer, CHD, stroke, and osteoporosis. Quitting smoking even at advanced ages reduces the risk of most of them. The risk of CHD and stroke decreases almost as soon as smoking is stopped, and in 5 years an ex-smoker is not much more likely to suffer these diseases than a person who has never smoked. After a smoker has stopped, it takes about 15 years before the risk of lung cancr is similar to that of lifetime nonsmokers. However, it is of interest that the risks due to smoking may be overcome, in part, by exercise regimens that maintain a high level of physical fitness. The likelihood that cognitive function will be maintained into advanced ages increases with the amount of education the individual had in his/her youth. There is reason to believe that education at advanced ages also enhances cognitive function. Those who do not hae close family and/or close friends are more likely to become ill and to have a relatively short length of life. The best predictors of the well-being of an elderly person are the frequency of visits with family and friends and the extent of participation in organizations. Assisting a person with a task that he or she is able to do may decrease the individual's confidence in his/her ability to do the task. Whenever possible, the assistance should be rendered by encouraging the person to do the task for himself/herself
education and social support

Therapy : gerontotherapeutics / gerontotherapy : therapeutic management of aging persons designed to retard and prevent the development of many of the aspects of senescence. Successful aging is defined in terms of ability of the individual to maintain the following characteristics into advanced ages : low risk of disease and disease-related disability, high mental and physical functioning, and active engagement with life

a systematic review found that integrated care experiments in elderly people could reduce rates of admission, though the effects are highly dependent on the system of care and the nature of the intervention^ref. Case management of patients at risk of admission has also been proposed as a way of reducing the risk of readmission, but a recent review found only limited evidence that this approach reduces use of health services. One way of identifying patients at risk of admission is to select those with recent emergency or unscheduled admissions. Published risk assessment tools identify past admissions, especially unscheduled admissions, as important risk factors for subsequent admission^{ref1,
ref2,
ref3}. For example, a history of two or more emergency admissions in the previous year is the principle factor used to identify patients to enrol in an intensive case management programme for older people currently being introduced in the United Kingdom by Evercare^ref, an arm of the US healthcare provider United Health Group. This initiative uses specially trained nurses to monitor vulnerable older people at home and is modelled on similar Evercare interventions in the United States^ref that are associated with reduced risk of readmission to hospital^ref. Evercare is not alone in using history of unplanned admissions as a means of identifying patients at risk of future admission. The same approach has been used as the entry criterion for several trials^{ref1,
ref2,
ref3} and as one of the criteria for case management in the new NHS policy on long term conditions^ref. People aged 65 with 2 of more emergency admissions are responsible for 38% of emergency hospital admissions in their age group. Admissions in people age 65 with two of more emergency admissions fall in subsequent years without any intervention and account for < 10% of admissions in the following year. The effectiveness of admission avoidance schemes cannot be judged by tracking admission rates without careful comparison with a control group.
28% of all prescribed drugs in the UK are consumed by the 7% of the population aged over 75^ref; 6.5% of hospital admissions have recently been shown to be related to adverse drug reactions, and these are significantly more likely to occur in older patients^ref. This may be due to a combination of factors, including polypharmacy and age related physiological changes. Older patients can also have considerable problems with adhering to their drug regimens—up to 50% of prescribed drugs are estimated to be not taken as prescribed^ref. The national service framework for older people and the NHS plan recommend regular medication reviews for older patients to maximise therapeutic benefit and minimise potential harm. Historically, UK studies of medication review have focused on prescribing outcomes rather than effects on hospital admissions^ref1,
ref2. An Australian study of a home based medication review-type intervention showed a 25% reduction in admissions and a reduction in deaths outside hospital^ref. A UK trial suggests that home based medication review for older people recently discharged from hospital increased, rather than decreased, hospital admissions. It also seemed to worsen patients' quality of life compared with controls. The exact mechanism for this result is not apparent. Patients may have adhered better to their drugs, with a resultant increase in side effects or drug interactions. Alternatively, our intervention may have provoked better understanding and help seeking behaviour. Either way, a growing body of evidence suggests that further research is necessary to elucidate the most effective form and detailed effects of medication review. The recommendation in the national service framework for older people that this should be widely introduced in primary care seems to lack a clear evidence base. Indeed, another study using pharmacists to improve discharge from hospital found no effect on adherence^ref. Previous studies have shown that interventions of this type by pharmacists tend to increase adherence to prescribed drugs^{ref1,
ref2,
ref3,
ref4}. 2 large UK studies of community based medication showed non-significant decreases in admissions^ref1,
ref2 whereas a third showed a non-significant increase in admissions^ref. These results, in combination with ours, indicate that it cannot be assumed that community based medication review necessarily reduces admissions, despite evidence from overseas.11 Although our finding on mortality is potentially encouraging, UK results on this outcome are equivocal, with mixed, non-significant results^{ref1,
ref2,
ref3}. Evidence in the field of medication review is growing rapidly. More positive results seem to have resulted from interventions focused on diseases such as heart failure^ref. Alternative models to home visiting also exist, including reviews within a general practice surgery^ref. Such a review has the advantage of access to full patient records, potentially allowing a more thorough clinical medication review than was possible within this study. In addition, it allows pharmacists to build up a close working relationship with general practitioners, which is vital if the pharmacists' recommendations are to be followed.

Bibliography :

Edward J.Masoro, Ph.D : Challenges of biological aging; Springer Publishing Company, New York, 1999
Nature Insight Ageing in Nature Vol.408 9 November 2000

Web resources :

American Academy of Anti-Aging Medicine (A4M)

American Board Of Anti-Aging Medicine (ABAAM)

Asia-Oceanic Federation of Anti-Aging Medicine (AOFAAM)
National Institute on Ageing (NIA) at NIH

Aging theories

Aging at CDC
Science of Aging Knowledge Environment (SAGE) at Science
A Memorial to Mme Jeanne Calment
GSA's Centenarian page
The Oldest Human Beings (extensive list)
Noted nonagenarians and centenarians
New England Centenarian Study
Korean Academy of Anti-Aging Medicine (KA3M)
Usenet bionet.molbio.ageing
World Academy of Anti-Aging Medicine (WAAAM)
Journals : Ageing Cell