Aging :- Topic for the medical Student.pptx

Help is taken from the Harrison medicine book

1. Aging ( “What does not kill me makes me stronger”) …Nietzsche By:- dr. Vishwajit kumar M.D. (PHYSIOLOGY) DEPARTMENT OF PHYSIOLOGY A.N.M.M.COLLEGE,Gaya

2. Definitions of Aging Aging is easy to recognize but difficult to define It is a progressive process associated with declines in structure and function, impaired maintenance and repair systems, increased susceptibility to disease and death, and reduced reproductive capacity.

3. Definitions of aging rarely acknowledge the possibility that some of those biological and functional changes with aging might be adaptive or even reflect improvement and gain . Nor do they emphasize the impact of aging on responses to medical treatments.

4. EVOLUTIONARY MECHANISMS FOR AGING At the most basic level, living things have only two approaches to maintain their existence: immortality or reproduction In a changing environment, reproduction combined with a finite life span has proved to be the successful strategy.

5. There are some species of plants and animals that do not appear to age, or at least they undergo an extremely slow aging process , termed “negligible senescence.” The mortality rates of these species are relatively constant with time and they do not display any obvious phenotypic changes of aging. Conversely, some living things undergo programmed death immediately after reproduction such as annual plants and semelparous (   reproducing or breeding only once in a lifetime ) animals

6. The typical features of aging

7. the major classical evolutionary theories of aging include Programmed death. Mutation accumulation. Antagonistic pleiotropy. Life history theory Disposable soma theory.

8. aspects of aging might be adaptive and raise the possibility that evolution can act on the aging process in a positive way. Grandmother hypothesis Mother’s curse. Adaptive senectitude.

9. Programmed death . The first evolutionary theory of aging was proposed by Weismann in 1882 . This theory states that aging and death are programmed and have evolved to remove older animals from the population so that environmental resources such as food and water are freed up for younger members of the species

10. Mutation accumulation . This theory was proposed by Medawar in 1952 . Natural selection is most powerful for those traits that influence reproduction in early life, and therefore, the ability of evolution to shape our biology declines with age. Germline mutations that are deleterious in later life can accumulate simply because natural selection cannot act to prevent them.

11. Antagonistic pleiotropy George C. Williams extended Medawar’s theory when he proposed that evolution can allow for the selection of genes that are pleiotropic, i.e., beneficial for survival and reproduction in early life, but harmful in old age . For example, genes for sex hormones are necessary for reproduction in early life but contribute to the risk of cancer in old age

12. Life history theory Evolution is influenced by the way that limited resources are allocated to all aspects of life including development, sexual maturation, reproduction, number of offspring, and senescence and death. Therefore “trade-offs” occur between these phases of life

13. . For example, in a hostile environment, survival is highe s t for those species that have large numbers of offspring and short life span while in a safe and abundant environment, survival is highest for those species that invest resources in a smaller number of offspring and a longer life

14. Disposable soma theory . Kirkwood and Holliday in 1979 combined many of these ideas in the disposable soma theory of aging. There are finite resources available for the maintenance and repair of both germ and soma cells so there must be a trade-off between germ cells (i.e., reproduction) versus soma cells (i.e., longevity and aging).

15. The soma cells are disposable from an evolutionary perspective, so they accumulate damage that causes aging while resources are preferentially diverted to the maintenance and repair of the germ cells

16. Grandmother hypothesis . The grandmother hypothesis proposed by Hamilton in 1966 describes how evolution can enhance old age. In some animals, including humans, the survival of multiple, dependent offspring is beyond the capacity and resources of their mother. In this situation, the presence of a long-lived grandmother who shares in care of her grandchildren can have a major impact on their survival. These children share some of the genes of their grandmother including those that promoted their grandmother’s longevity.

17. Mother’s curse. Mitochondrial dysfunction is a key component of the aging process. Mitochondria contain their own DNA and are only passed on from mother to child, because sperm cells contain almost no mitochondria. Therefore, natural selection can only act on the evolution of mitochondrial DNA in females. The “mother’s curse” of the maternal inheritance of mitochondrial DNA might explain why females live longer and age more slowly than males

18. Adaptive senectitude . Many traits that are harmful in younger humans such as obesity, hypertension, oxidative stress, and declines in growth hormone and insulin-like growth factor type I (IGF-1) paradoxically appear to be associated with greater survival and function in old age. Perhaps driven by the grandmother effect, this might represent “adaptive senectitude” or “reverse antagonistic pleiotropy” whereby some traits that are harmful in young people become beneficial in older people

19. CELLULAR PROCESSES THAT ACCOMPANY AGING Oxidative Stress and the “Free Radical Theory of Aging ” Mitochondrial Dysfunction Telomere Shortening and Replicative Senescence Altered Gene Expression, Epigenetics, and microRNA Impaired Autophagy and Proteostasis

20. Oxidative Stress and the “Free Radical Theory of Aging Free radicals are chemical species that are highly reactive because they contain unpaired electrons Oxidants are oxygen-based free radicals that include the hydroxyl free radical, superoxide, and hydrogen peroxide. Most cellular oxidants are waste products generated by mitochondria during the production of ATP from oxygen.

21. More recently, the role of oxidants in cellular signaling and inflammatory responses has been recognized. Unchecked, oxidants can generate chain reactions leading to widespread damage to biological molecules. Cells contain numerous antioxidant defense mechanisms to prevent such oxidative stress including enzymes (superoxide dismutase, catalase, glutathione peroxidase) and chemicals (uric acid, ascorbate).

22. In 1956, Harman proposed the “free radical theory of aging” whereby oxidants generated by metabolism or irradiation are responsible for age-related damage . It is now well established that old age in most species is associated with increased oxidative stress, for example to DNA (8-hydroxyguanosine derivatives), proteins (carbonyls), lipids ( lipoperoxides , malondialdehydes), and prostaglandins ( isoprostanes ).

23. Conversely, many of the cellular antioxidant defense mechanisms including the antioxidant enzymes decline in old age. The free radical theory of aging has spawned numerous studies of supplementation with antioxidants such as vitamin E to delay aging in animals and humans . However, meta-analyses of human clinical trials performed to treat and prevent various diseases with antioxidant supplements indicate that they have no effect on, or may even increase, mortality.

24. Mitochondrial Dysfunction Aging is characterized by altered mitochondrial production of ATP and oxygen-derived free radicals. This leads to a vicious cycle mediated by accumulation of oxidative injury to mitochondrial proteins and DNA. With age, the number of mitochondria in cells decreases and there is an increase in their size (megamitochondria ) associated with other structural changes including vacuolization and disrupted cristae

25. . These morphological aging changes are linked with decreased activity of mitochondrial complexes I, II, and IV and decreased ATP production. Of all of the complexes involved in ATP production, the activity of complex IV (COX) is usually reported to be most impaired in old age.

26. Reduced energy production is linked with generation of hydrogen peroxide and superoxide radicals leading to oxidative injury to mitochondrial DNA and accumulation of carbonylated mitochondrial proteins and mitochondrial lipoperoxides . As well as being implicated in the aging process, common geriatric syndromes including sarcopenia, frailty, and cognitive impairment are associated with mitochondrial dysfunction.

27. Telomere Shortening and Replicative Senescence Cells that are isolated from animal tissue and grown in culture only divide for a certain number of times before entering a senescent phase. This number of divisions is known as the Hayflick limit and tends to be less in cells isolated from older animals compared to younger animals . It has been suggested that aging in vivo might in part be secondary to some cells ceasing to divide because they have reached their Hayflick limit

28. . Senescent cells produce a variety of cytokines, chemokines, and proteases, termed the senescence-associated secretory phenotype (SASP), that are major drivers of age-related inflammation. Eliminating senescent cells delayed aging in mice. On the other hand, cellular senescence may have a role in preventing proliferation of cells at risk of malignant transformation.

29. One mechanism for replicative senescence relates to telomeres. Telomeres are repeat sequences of DNA at the end of linear chromosomes that shorten by around 50–200 base pairs during each cell division by mitosis. Once telomeres become too short, cell division can no longer occur. This mechanism contributes to the Hayflick limit and has been called the cellular clock

30. . There are some studies that suggest that the length of telomeres in circulating leukocyte s (leukocyte telomere length, LTL) decreases with age in humans. However, the aging process also occurs in tissues that do not undergo repeated cell division such as neurons.

31. Altered Gene Expression, Epigenetics, and microRNA The expression of many genes and proteins changes during the aging process. These changes are complicated and vary between species and tissue. Such heterogeneity reflects increasing dysregulation of gene expression with age while appearing to exclude a programmed and/or uniform response.

32. With old age, reductions in the expression of genes and proteins associated with mitochondrial function and increased expression of those involved with inflammation, genome repair, and oxidative stress are noted Several factors control the regulation of gene and protein expression that change with aging. These include the epigenetic state of the chromosomes (e.g., DNA methylation and histone acetylation) and microRNAs (miRNAs). DNA methylation correlates with age, although the pattern of change is complex.

33. Histone acetylation is regulated by many enzymes including Sirtuin 1 (SIRT1 ), a protein that has marked effects on aging and the response to dietary restriction in many species. miRNAs are a very large group of noncoding lengths of RNA (18–25 nucleotides) that inhibit translation of multiple different mRNAs through binding their 3’ untranslated regions (3’UTRs). The expression of miRNAs usually decreases with aging and is altered in some age-related diseases.

34. Specific miRNAs linked with aging pathways include miR-21 (associated with target of rapamycin pathway) and miR-1 (associated with insulin/insulin-like growth factor 1 pathway).

35. Impaired Autophagy and Proteostasis Cells can remove damaged macromolecules and organelles in a number of ways, often generating cellular energy as a by-product. Intracellular degradation is undertaken by the lysosomal system and the ubiquitin proteasomal system . Both are impaired with aging, leading to the accumulation of waste products that alter cellular functions.

36. Such waste products include lipofuscin , a brown auto-fluorescent pigment found within lysosomes of most cells in old age and often considered to be one of the most characteristic histological features of aging cells. Lysosomes are organelles that contain proteases, lipases, glycases , and nucleotidases that degrade intracellular macromolecules, membrane components, organelles, and some pathogens through a process called autophagy

37. The lysosomal process most impaired with aging is macroautophagy , which is regulated by numerous autophagy-related genes . Proteostasis refers to the maintenance of protein quality through regulation of protein folding and protein degradation . Chaperone s orchestrate appropriate folding of proteins while degradation involves ubiquitin tagging, proteases, and the unfolded protein response.

38. . With aging damaged, aggregated and misfolded proteins increase because of age-related changes in proteostasis . This may contribute to the aggregation of proteins such as tau, β-amyloid, α-synuclein in age-related neurodegenerative diseases such as dementia and Parkinson’s disease

39. Schema linking evolution, cellular and tissue changes with aging

40. AGING CHANGES IN SPECIFIC TISSUES THAT PREDISPOSE TO DISEASE Aging changes in some tissues increase susceptibility to age-related disease as a secondary or downstream phenomenon . In humans, this includes, the immune system (leading to increased infections and autoimmunity), hepatic detoxification (leading to increased exposure to disease-inducing endobiotics and xenobiotics), the endocrine system (leading to hypogonadism and bone disease), and the vascular system (leading to segmental or global ischemic changes in many tissues)

41. Inflamm-aging and Immunosenescence Old age is associated with increased background levels of inflammation including blood measurements of C reactive protein (CRP), erythrocyte sedimentation rate (ESR), and cytokines such as interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFα). This has been termed “ inflamm -aging” and elevated IL-6 in particular has been associated with frailty and dementia .

42. T cells are less numerous because of age-related atrophy of the thymus, while B cells overproduce autoantibodies, leading to the age-related increase in autoimmune diseases and gammopathies. Thus, older people are generally considered to be immunucompromised and have reduced responses to infection (fever, leukocytosis) with increased mortality.

43. Detoxification and the Liver Old age is associated with impaired detoxification of various disease-causing endobiotics (e.g., lipoproteins) and xenobiotics (e.g., neurotoxins and carcinogens) leading to increased systemic exposure. In humans, the liver is the major organ for the clearance of such toxins.

44. Hepatic clearance of many substrates is reduced in old age as a consequence of reduced hepatic blood flow, impaired hepatic microcirculation and, in some cases, reduced expression of xenobiotic metabolizing enzymes. These changes in hepatic detoxification also increase the likelihood of increased blood levels of, and adverse reactions to, medications.

45. Endocrine System Hormonal changes with aging have been a focus for aging research for over a century, partly because of the erroneous belief that supplementation with sex hormones will delay aging and rejuvenate older people. There are age-related reductions in sex steroids, growth hormone, IGF-1, and dehydroepiandrosterone (DHEA).

46. These hormonal changes may contribute to some features of aging such as sarcopenia and osteoporosis but also provide protection against cancer and cardiovascular disease. Adverse effects of long-term hormonal supplementation outweigh any potential beneficial effects on life span

47. Vascular Changes There is a continuum from vascular aging through to atherosclerotic disease, present in many, but not all, older people. Vascular aging changes overlap with the early stages of hypertension and atherosclerosis, with increasing arterial stiffness and vascular resistance.

48. This contributes to myocardial ischemia and strokes but also appears to be associated with geriatric conditions such as dementia, sarcopenia, and osteoporosis In these conditions, impaired exchange between blood and tissues is a common pathogenic factor. For example, the risk of Alzheimer’s disease and dementia is increased in patients with risk factors for vascular disease, and pathological evidence for microvascular changes is seen in postmortem studies of brains of people with established Alzheimer’s disease.

49. Similarly, strong epidemiological links have been found between osteoporosis and standard vascular risk factors, while significant age-associated changes are in the microcirculation of osteoporotic bone. Sarcopenia might also be related to the effects of age on the muscle vasculature, which is altered in old age

50. . The sinusoidal microcirculation of the liver becomes markedly altered during aging ( pseudocapillarization ), which influences hepatic uptake of lipoproteins, insulin, and other substrates. In fact, it has often been overlooked that in his original exposition of the free radical theory of aging, Harman proposed that the primary target of oxidative stress was the vasculature and that many aging changes were secondary to impaired exchange across the damaged blood vessels.

51. GENETIC INFLUENCES ON AGING There is variability in aging and life span in populations of genetically identical species such as mice that are housed in the same environment. The heritability of life span in human twin studies is estimated to be only 25% (although there is stronger hereditary contribution to extreme longevity).

52. . These two observations indicate that the cause of aging is unlikely to lie only within the DNA code. On the other hand, genetic studies initially undertaken in the nematode worm C. elegans and, more recently, in models from yeast to mice have shown that manipulating genes can have profound effects on the rate of aging Perhaps surprisingly, this can often be generated by variability in single genes, and for some genetic mechanisms, there is very strong evolutionary conservation.

53. Gene Studies in Long-Lived Humans The main genes that have been consistently associated with increased longevity in human candidate gene studies are APOE and FOXO3A . ApoE is an apoprotein found in chylomicrons while the ApoE4 isoform is a risk factor for Alzheimer’s disease and cardiovascular disease, which might explain its association with reduced life span.

54. FOXO3A is a transcription factor involved in the insulin/IGF-1 pathway, and its homolog in C. elegans, daf16, has a marked impact on aging in these nematodes. Genomewide association studies (GWASs) of centenarians have confirmed the association of longevity with APOE.

55. GWAS has been used to identify a range of other single nucleotide polymorphisms (SNPs) that might be associated with longevity including SNPs in the sirtuin genes and the progeroid syndrome genes, LMNA and WRN. Gene set analysis of GWAS studies has shown that both the insulin/IGF-1 signaling pathway and the telomere maintenance pathway are associated with longevity.

56. One group of particular interest are people with Laron-type dwarfism. These people have mutations in the growth hormone receptor that causes severe growth hormone resistance. In mice, similar knockout of the growth hormone receptor (GHRKO mice, Methuselah mice) is associated with extremely long life. Therefore, subjects with Laron syndrome have been carefully studied and it was found that they have very low rates of cancer and diabetes mellitus, and possibly, longer lives

57. Nutrient-Sensing Pathways Many living things have evolved to respond to periods of nutritional shortage and famine by increasing cellular resilience and delaying reproduction until food supply becomes abundant once again. This increases the chances of reproductive success and survival of offspring. Lifelong food shortage, often termed “caloric restriction (CR)” (or “dietary restriction”), increases life span and delays aging in many animals, probably as a side effect of this famine response

58. Many of the genes and pathways that regulate the way that cells respond to nutritional undersupply have been identified , initially in yeast and C. elegans. In general, manipulation of these pathways (through genetic knockout or overexpression, or pharmacological agonists and antagonists) alters the aging benefits of CR, and in some cases, the life span of animals on normal diets.

59. These pathways are all very influential cellular “switches” that control a wide range of key functions including protein translation, autophagy, mitochondrial function and bioenergetics, and the cellular metabolism of fats, proteins, and carbohydrates. The discovery of these nutrientsensing pathways has led to targets for pharmacological extension of life span.

60. Mitochondrial Genes Mitochondrial function is influenced by genes located both in the mitochondria ( mtDNA ) and the nucleus. mtDNA is considered to have a prokaryotic origin and is highly conserved across taxa. It forms a circular loop of 16,569 nucleotides in humans. Aging is associated with increased frequency of mutations in mtDNA as a consequence of its high exposure to oxygen-derived free radicals and relatively inefficient DNA repair machinery.

61. Nuclear DNA encodes ~1000–1500 genes for mitochondrial function including genes involved with oxidative phosphorylation, mitochondrial metabolic pathways, and enzymes required for biogenesis. These genes are thought to have originated in mtDNA but subsequently translocated to the nucleus and, unlike mtDNA genes, their sequence is stable with aging.

62. Genetic manipulation of mitochondrial genes in animals influences aging and life span. In C. elegans, many mutants with defective electron transfer chain function have increased life span. The mtDNA “mutator” mice which lack the mtDNA proofreading enzyme have increased mtDNA mutations and premature aging, while overexpression of mitochondrial uncoupling proteins leads to longer life span

63. In humans, hereditary variability in mtDNA is associated with diseases ( mitochondriopathies such as Leigh’s disease) and aging. For example, in Europeans, mitochondrial DNA haplogroup J (haplogroups are combinations of genetic variants that exist in specific populations) is associated with longevity, and haplogroup D is overrepresented in Asian centenarians.

64. Nuclear DNA Genomic DNA damage accumulates in cells with aging while genetic progeroid conditions such as Werner’s syndrome and HGPS are associated with impaired DNA maintenance and repair. Age-related DNA changes include mutations, chromosomal aneuploidy, copy number variations, and telomere shortening. Apart from telomere attrition, these changes are random and vary between cells, and may contribute to age-related cancers.

65. Pharmacological Interventions to Delay Aging and Increase Life Span Virtually all obese people know that stable weight reduction will reduce their elevated risk of cardiometabolic disease and enhance their overall survival, yet only 20% of overweight individuals are able to lose 10% weight for a period of at least 1 year.

66. Even in the most motivated people (such as the “Cronies” who deliberately attempt long-term CR in order to extend their lives), longterm CR is extremely difficult. Thus, focus has been directed at the possibility of developing medicines that replicate the beneficial effects of CR without the need for reducing food intake (“CR-mimetics,”

67. ■ STRATEGIES THAT INCREASE HEALTH SPAN AND DELAY AGING Life span is inevitably accompanied by functional decline, steady increase of a plethora of chronic diseases, and ultimately death. For millennia, it has been a dream of mankind to prolong both life span and health span.

68. Developed countries have profited from the medical improvements and their transfer to public health care systems—as well as from better living conditions derived from their socioeconomic power—to achieve remarkable increases in life expectancy during the last century. The prevalence of age-related pathologies represents a major threat as well as an economic burden that urgently needs effective interventions.

69. Over the past two decades, this interest has taken root in the fact that many of the molecular mechanisms underlying aging are interconnected and linked with pathways that cause disease, including cancer, cardiovascular and neurodegenerative disorders. Unfortunately, among the many proposed aging interventions, only a few have reached a certain age themselves.

70. Results often lack reproducibility because of a simple inherent problem Interventions in aging research take a lifetime to assess. Experiments lasting the lifetime of animal models are prone to develop artifacts, increasing the possibilities and time windows for experimental discrepancies. Some inconsistencies in the field arise from overinterpreting life span-shortening models and scenarios as being accelerated aging.

71. Intervention COTEGORIES Many substances and interventions have been claimed to be antiaging throughout history and into the present ,ONLY 3 have proven benefits CR (Caloric Restriction)and fasting regimens, some pharmacotherapies (resveratrol, rapamycin, spermidine, and metformin), and exercise.

72. Caloric Restriction CR is defined as a reduction in the total caloric intake, usually of about 30% and without malnutrition . CR reduces the release of growth factors such as growth hormone, insulin, and IGF-1, which are activated by nutrients and have been shown to accelerate aging and enhance the probability for mortality in many organisms Effects of CR on aging were first discovered by McCay in 1935 long before the effects of such hormones and growth factors on aging were recognized

73. The cellular pathways that mediate this remarkable response include the nutrient sensing pathways (mTOR, AMPK, insulin/IGF-1, and sirtuins ) as well as transcription factors (FOXO in D. melanogaster and daf-16 in C. elegans). The transcription factor Nrf2 appears to confer most of the anticancer properties of CR in mice, even though it is dispensable for life span extension

74. In humans, CR is associated with increased life and health span. This is most convincingly demonstrated in Okinawa, Japan, where one of the most long-lived human populations resides. In comparison to the rest of the Japanese population, Okinawan people usually combine an above-average amount of daily exercise with a below-average food intake.

75. However, when Okinawan families move to Brazil, they adopt a Western lifestyle that affects both exercise and nutrition, causing a rise in weight and a reduction in life expectancy by nearly two decades CR changes many aspects of human aging that might influence life span such as the transcriptome, hormonal status (especially IGF-1 and thyroid hormones), oxidative stress, inflammation, mitochondrial function, glucose homeostasis, and cardiometabolic risk factors. Epigenetic modifications are an emerging target for CR.

76. substantial side effects of cr Prolonged reduction of calorie intake may decrease fertility and libido, impair wound healing, reduce the potential to combat infections, and lead to amenorrhea and osteoporosis

77. PERIODIC FASTING How can CR be translated to humans in a socially and medically feasible way? A whole series of periodic fasting regimens are asserting themselves as suitable strategies, among them the alternate-day fasting diet, the “ five:two ” intermittent fasting diet, and a 48-h fast once or twice each month.

78. Periodic fasting is psychologically more viable, lacks some of the negative side effects and is only accompanied by minimal weight loss Several lines of evidence indicate that intermittent fasting regimens exert antiaging effects. For example, improved morbidity and longevity were observed among Spanish home nursing residents who underwent alternate-day fasting.

79. Even rats subjected to alternate-day fasting live up to 83% longer than normally fed control animals and one 24-h fasting period every 4 days is sufficient to generate life span extension Repeated fasting and eating cycles may circumvent the negative side effects of sustained CR. This strategy may even yield effects despite extreme overeating during the nonfasting periods

80. From an evolutionary point of view, this kind of feeding pattern may reflect mammalian adaptation to food availability : overeating in times of nutrient availability (e.g., after a hunting success) and starvation in between This is how some indigenous peoples who have avoided Western lifestyles live today; those who have been investigated show limited signs of age-induced diseases such as cancer, neurodegeneration, diabetes, cardiovascular disease, and hypertension.

81. Fasting exerts beneficial effects on health span by minimizing the risk of developing age-related diseases including hypertension, neurodegeneration, cancer, and cardiovascular diseases The most effective and rapid repercussion of fasting is reduction in hypertension. Two weeks of water-only fasting resulted in a blood pressure below 120/80 mmHg in 82% of subjects with borderline hypertension. Ten days of fasting cured all hypertensive patients who had been taking antihypertensive medication previously

82. Periodic fasting dampens the consequences of many age-related neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and frontotemporal dementia Fasting cycles are as effective as chemotherapy against certain tumors in mice. In a combination with chemotherapy, fasting protected mice against the negative side effects of chemotherapeutic drugs, while it enhances their efficacy against tumors.

83. Pharmacological Interventions to Delay Aging and Increase Life Span Focus has been directed at the possibility of developing medicines that replicate the beneficial effects of CR without the need for reducing food intake (“ CR-mimetics) . MEDICINES ARE resveratrol, rapamycin, spermidine, and metformin

84. Chemical structure of four agents that have been shown to delay aging in experimental animal models.

85. Exercise and Physical Activity In humans and animals, regular exercise reduces the risk of morbidity and mortality An increase in aerobic exercise capacity, which declines during aging, is associated with favorable effects on blood pressure, lipids, glucose tolerance, bone density, and depression in older people. Likewise, exercise training protects against aging disorders such as cardiovascular diseases, diabetes mellitus, and osteoporosis.

86. Exercise is the only treatment that can prevent or even reverse sarcopenia (age-related muscle wasting). Even moderate or low levels of exercise (30 min walking per day) have significant protective effects in obese subjects . In older people, regular physical activity has been found to increase the duration of independent living.

87. While clearly promoting health and quality of life, regular exercise does not extend life span. Furthermore, the combination of exercise with CR has no additive effect on maximal life span in rodents. On the other hand, alternate-day fasting with exercise is more beneficial for the muscle mass than single treatments alone.

88. In nonobese humans, exercise combined with CR has synergistic effects on insulin sensitivity and inflammation. From the evolutionary perspective, the responses to hunger and exercise are linked: when food is scarce, increased activity is required to hunt and gather

89. During ischemic preconditioning in humans, short periods of ischemia protect the brain and the heart against a more severe deprivation of oxygen and subsequent reperfusion-induced oxidative stress. Similarly, the lifelong and periodic exposure to various stressors can inhibit or retard the aging process

90. CONCLUSIONS There is an urgent need to develop strategies based on aging biology that delay aging, reduce the onset of age-related disorders, and increase health span for future generations. Interventions related to nutrition and those drugs that act on nutrient-sensing pathways are being developed and, in some cases, are already being tested in humans.

91. Physiological changes in geriatric age groups.

92. Thank you all Patience is when you’re supposed to get mad, but you choose to understand.” —Anonymous