Uploaded byssuser880f82
PDF, PPTX72 views

ageing ppt.pdf

This document provides an overview of the biology of aging, covering general concepts, theories of aging, aging at the cellular and molecular level, and interventions in the aging process. It discusses topics such as the universality and rates of senescence across species, primary aging processes, theories including evolutionary, genetic/developmental, and oxidative damage theories. It covers cellular aging concepts such as replicative senescence, telomere shortening, and the role of telomerase. It also discusses pro-longevity factors seen in long-lived human populations and exceptions to characteristics typically associated with aging.

Embed presentation

Download as PDF, PPTX
The Biology of Aging: An Overview Robert J. Pignolo, M.D., Ph.D. Assistant Professor of Medicine Division of Geriatric Medicine Fellow, Institute on Aging
Biology of Aging: An Overview • General Concepts Th i f A i • Theories of Aging • Aging at the Cellular and Molecular Level Level • Interventions in the Aging Process
Biology of Aging: An Overview • General Concepts Th i f A i • Theories of Aging • Aging at the Cellular and Molecular Level Level • Interventions in the Aging Process
Aging v. Senescence Beneficial Neutral Deleterious Beneficial Neutral Deleterious
Universality of Aging • No evidence that prokaryotes undergo senescence • Populations of single-celled eukaryotic organisms are immortal organisms are immortal • In multicellular organisms, senescence occurs in those that undergo somatic cell occurs in those that undergo somatic cell differentiation Masoro, E in Handbook of Physiology, Aging, Section 11:3-21 (1995).
Rates of Senescence • RAPID: occurs abruptly after maturation (e.g. nematodes, flies) or soon after reproduction (e.g., annual plants, Pacific salmon) • GRADUAL: slow but persistent deterioration after i i ll l l l maturation in all placental mammals • NEGLIGIBLE: no clear evidence for t t ti l i i t lit t ( postmaturational increases in mortality rate (e.g., clams, trees, fish, reptiles) Finch, CE in Longevity, Senescence, and the Genome (1994).
Q: Which of the following is true with regard to primary aging processes? They are deteriorative changes over time in the relative absence of disease or injury. Protection against premature death underlies survival increases that would otherwise be reduced secondary to primary aging processes. They do not influence maximum life span. They are not thought to be the underlying cause of senescence across species.
Primary Aging Processes • Deteriorative changes over time in the relative absence of disease or injury j y • Influence maximum life span • Thought to be the underlying cause of • Thought to be the underlying cause of senescence across species
Primary aging processes occur in the absence of disease Bill Collins World’s Fastest 50 Year Old World Records: 5,000 M Run 450 d (m/min) 250 300 350 400 Men Women Speed 50 100 150 200 Age (yr) 20 40 60 80 100 Age 17 Age 52
Median Length of Life • Age at which there are as many individuals with shorter life spans as there are with p longer ones • Protection from premature death underlie Protection from premature death underlie survival increases • Thought NOT to reflect primary aging • Thought NOT to reflect primary aging processes
Maximum Life Span • Age of the longest-lived survivors of a cohort or population p p • For humans, operationally considered to be the oldest age reached by 1 in 100 million the oldest age reached by 1 in 100 million people • Considered to be inversely proportional to • Considered to be inversely proportional to the rate of aging of a population
Q: All of the following resulted in a dramatic increase in average life span in the early 1900s except: Sanitation Immunization Immunization Better nutrition Antibiotics Antibiotics
Human Survivorship through History Pignolo, RJ & Forciea, MA, in Geriatric Secrets, pp 7-13 (2004)
Life Expectancy List by the United N ti (2005 2010) Nations (2005-2010) Rank Country Life expectancy at birth (years) Life expectancy at birth (years) Life expectancy at birth (years) Overall Male Female 1 Japan 82.6 78.0 86.1 2 Hong Hong 82.2 79.4 85.1 3 Iceland 81.8 80.2 83.3 4 Switzerland 81.7 79.0 84.2 5 Australia 81.2 78.9 83.6 6 Spain 80.9 77.7 84.2 7 Sweden 80.9 78.7 83.0 8 Israel 80.7 78.5 82.8 9 Macau 80.7 78.5 82.8 10 France (metro) 80.7 77.1 84.1 11 Canada 80.7 78.3 82.9 12 Italy 80.5 77.5 83.5 36 United States 78.3 75.6 80.8
Life Expectancy at birth
Male Life Expectancy
Longest-lived Humans J C l t (F ) Ch i ti M t Jeanne Calment (France) Lived to age 122 Christian Mortensen (Danish-American) Lived to age 115 Robine, J-M & Allard, M, Science 279: 1834-5 (1998). Deianna, L et al. JAGS 50: 2098-9 (2002).
Q: Examples of long-lived human populations point to which of the following pro-longevity factor(s): Q: Examples of long lived human populations point to which of the following pro longevity factor(s): Genetic pre-disposition Dietary practices Spirituality Conformity to beneficial health practices All of the above
The places where people live the longest • Okinawa, Japan • Ovodda, Sardinia , (Italy) • Loma Lida, CA (USA)
Keys to longevity-Okinowa • “hara haci bu” • Rainbow diet • Diet: soy > fish, meat, eggs, dairy • BMI 20.4 • ~1200 cal diet • DHEA levels decline more slowly
Keys to longevity- Ovodda, Sardinia • As many men live to 100 as women • Sardinians who emigrated • Sardinians who emigrated at 20, 30 or 40 years of age still manage to reach 100 100 • Descended from only a few original settlers – i l t d i t b di isolated, interbreeding • G6PD deficiency, other genetic traits?
Keys to longevity- Loma Linda, CA • Seventh Day Adventists • Members live 5-10 years longer than fellow citizens • No drinking or smoking • Many adhere to a vegetarian diet the church advises • Spiritual life • Regular churchgoers – of whatever faith - live longer • Significantly lower levels of stress hormones
Keys to longevity “H l ld li if “How long would you live if you were a Sardinian 7th Day Adventist who moved to Oki t 20 f ?” Okinawa at 20 years of age?”
Broken Limits to Life Expectancy Broken Limits to Life Expectancy Female life-expectancy in Japan has risen for 160 years at a steady 160 years at a steady pace of almost 3 m/yr! Oeppen & Vaupel Science 296: 1029-31 (2002)
Compression of Morbidity Fries, JF Ann Int Med 139:455-9 (2003)
Q: Which is true regarding morbidity with increased life span as reflected by disability trends? Morbidity increases with life extension. Morbidity remains the same with increased life span. Morbidity is compressed.
Q: Which of the following is true regarding the onset of age-related disease in centenarians? Age-related disease is delayed by almost one decade. Age-related disease occurs at about the same time in centenarians as in individuals with Age related disease occurs at about the same time in centenarians as in individuals with average life expectancy. Age-related disease does not occur in centenarians. Age-related disease may occur at about the same time as in individuals with average life Age-related disease may occur at about the same time as in individuals with average life spans, may be delayed or even absent in centenarians.
Who are centenarians? Who are centenarians? Survivors D l Delayers Escapers
____________________________________________________________________________ Characteristics of Aging Examples ____________________________________________________________________________ Increased mortality after maturation Survival curves showing exponential Increased mortality after maturation Survival curves showing exponential increase in mortality with age Changes in biochemical composition of tissues Increases in lipofuscin or age pigment Increased cross-linking in extracellular g matrix molecules such as collagen Progressive, deteriorative physiologic changes Declines in glomerular filtration rate, maximal heart rate, vital capacity Decreased ability to adaptively respond to Decreased "first past" hepatic metabolism environmental changes Blunted maximal cardiac responses to exercise Increasing incidence of many diseases Ischemic heart disease, type II diabetes, osteoporosis, Alzheimer's disease ____________________________________________________________________________ Cristofalo, VJ, Gerhard, GS & Pignolo, RJ Surg. Clin. N. Am. 74: 1-21 (1994).
____________________________________________________________________________ Characteristics of Aging E ceptions Characteristics of Aging Exceptions ____________________________________________________________________________ Increased mortality after maturation Human age-specific mortality rates do not continue to increase exponentially at very advanced ages advanced ages Changes in biochemical composition of tissues Changes are quite heterogeneous from organ to organ within a specific individual and also from individual to individual ("usual" and "successful" aging) Progressive, deteriorative physiologic changes " " Decreased ability to adaptively respond to " " environmental changes Increasing incidence of many diseases Elimination of atherosclerosis and cancer as causes of death would only add about ten years to average life span and would not affect maximum life span potential ____________________________________________________________________________
Biology of Aging: An Overview • General Concepts Th i f A i • Theories of Aging • Aging at the Cellular and Molecular Level Level • Interventions in the Aging Process
Stochastic or Random Error Theories Genetic/ Developmental Th i Theories Evolutionary Theory Theories of Aging Theories of Aging
Cumulative Oxidative Damage during A i Aging Weindruch, R & Sohal, RS NEJM 337: 986-94 (1997).
Q: All of the following evidence supports a genetic basis for longevity, except: Common polymorphisms in the APOE gene have a modest effect on life span. There is high conservation of maximum life span seen between species There is high conservation of maximum life span seen between species . There are examples of exceptional longevity within families. Twin studies demonstrate that genetic differences likely account for about 50% of the Twin studies demonstrate that genetic differences likely account for about 50% of the variance in adult human life span.
Genetic Basis of Aging Theories Hi h ti f i lif • High conservation of maximum life span between species • Similarity of attained age between monozygotic twins compared to dizygotic twins or nontwin siblings • Examples of exceptional longevity within p p g y families • Subsets of aging features in human genetic Subsets of aging features in human genetic syndromes of premature aging
Most commonly described human segmental progeroid syndromes. Syndrome Incidence (per live Inheritance Mean life- Progeroid features Genome maintenance y (p birth) span (years) g defect Hutchinson- Gilford <1/1,000,000 Unknown ~13 Alopecia, sclerosis, wrinkling, soft tissue, cachexia, arteriosclerosis, diminished fat Laminin Werner <1/100 000 Autosomal 50 Alopecia, osteoporosis, malignancies, arteriosclerosis diabetes cataracts DNA helicase (RecQ like) Werner <1/100,000 recessive ~50 arteriosclerosis, diabetes, cataracts, telangiectasia, skin atrophy, graying of hair (RecQ-like), exonuclease Rothmund- Thomson <1/100,000 Autosomal recessive Normal ? Alopecia, malignancies, poikiloderma, cataracts, osteoporosis, graying of hair DNA helicase (RecQ-like) Cockayne ~1/100,000 Autosomal recessive ~20 Thin hair, cachexia, retinal degeneration, hearing loss, neurodegeneration (cerebellar ataxia), cataracts Transcription- coupled DNA repair cataracts repair Trichothiodys trophy <1/100,000 Autosomal recessive ~10 Cachexia, osteoporosis, cataracts, fragile hair, neurodegeneration (cerebellar ataxia) DNA repair, basal transcription Ataxia telangiectasia ~1/60,000 Autosomal recessive ~20 Skin atrophy/sclerosis, telangiectasia, immunodeficiencies, malignancies, graying of hair, poikiloderma, neurodegeneration DNA damage signaling protein kinase (cerebellar ataxia) protein kinase Down ~1/1,000 De novo ~60 Cataracts, graying of hair, alopecia, diminished subcutaneous fat, vision loss, neurodegeneration (Alzheimer-like), thyroid dysfunction Trisomy Adapted from Hasty, P et al. Science 299: 1355-59 (2003).
Evolutionary Theory • Risk of mortality increases with time after reproduction • Genes that confer early benefits on reproductive fitness are selected, even if they cause deleterious ff l i lif effects later in life • No selective pressure against genes that confer ti ff t l t i lif negative effects later in life • Strong pressure to retain genes that diminish l bilit i d ld lik vulnerability in young and old alike
Biology of Aging: An Overview • General Concepts Th i f A i • Theories of Aging • Aging at the Cellular and Molecular Level Level • Interventions in the Aging Process
Replication Potential of Normal Replication Potential of Normal Human Cells Soma Germ Line Post-mitotic cells Quiescent Stem cells Primative germ cells (e.g., spermatogonia) Post mitotic cells (e.g., neurons) Quiescent, Replication-competent Somatic cells (e.g., fibroblasts) Stem cells (e.g., early hematopoietic precurcurs, gut-lining cells) No division Finite division Potentially unlimited cell division No division Finite division Potentially unlimited cell division
Q: Some characteristics associated with replicative senescence include all of the following except: Q: So e c a ac e s cs assoc a ed ep ca e se esce ce c ude a o e o o g e cept Apoptosis resistance Finite replicative life span Altered pattern of gene expression Promotion of intrinsic aging in all cell types Essentially irreversible growth arrest.
Cellular (Replicative) Senescence Stages in the in vitro life history of normal human diploid fibroblasts ll Number T r a n s f o r m a t i o n III Cumulative Cel II III IV Cell Aging C I V g g Adapted from Cristofalo, V.J. and Pignolo, R.J. Handbook of the Physiology of Aging, Oxford University Press, 1995.
Telomere Shortening with Telomere Shortening with Cellular Aging Harley, CB et al. , Nature 345: 458-60 (1990).
Telomere dysfunction capping unction/un mere dysfu Telom Persistent DNA damage Response
Replication Potential of Normal Replication Potential of Normal Human Cells Soma Germ Line Post-mitotic cells Quiescent Stem cells Primative germ cells (e.g., spermatogonia) Post mitotic cells (e.g., neurons) Quiescent, Replication-competent Somatic cells (e.g., fibroblasts) Stem cells (e.g., early hematopoietic precurcurs, gut-lining cells) T l Telomerase + No division Finite division Potentially unlimited cell division Telomerase - Telomerase - Telomerase + No division Finite division Potentially unlimited cell division
Aging in Telomerase-deficient mice • Age-dependent telomere shortening G i i bili • Genomic instability • Shortened life span • Reduced capacity to respond to stressors I d • Increased spontaneous malignancies Villi t f ll • Villi atropy of small intestine Rudolph, KL et al. Cell 96: 701-12 (1999).
Aging in Telomerase-deficient Humans Marciniak, R & Guarente, L Nature 413: 370-3 (2001).
Replication Potential of Normal Replication Potential of Normal Human Cells Soma Germ Line Post-mitotic cells Quiescent Stem cells Primative germ cells (e.g., spermatogonia) Post mitotic cells (e.g., neurons) Quiescent, Replication-competent Somatic cells (e.g., fibroblasts) Stem cells (e.g., early hematopoietic precurcurs, gut-lining cells) T l Telomerase + No division Finite division Potentially unlimited cell division Telomerase - Telomerase - Telomerase + No division Finite division Potentially unlimited cell division AGING
Replication Potential of Normal Replication Potential of Normal Human Cells Soma Germ Line Post-mitotic cells Quiescent Stem cells Primative germ cells (e.g., spermatogonia) Post mitotic cells (e.g., neurons) Quiescent, Replication-competent Somatic cells (e.g., fibroblasts) Stem cells (e.g., early hematopoietic precurcurs, gut-lining cells) T l Telomerase + No division Finite division Potentially unlimited cell division Telomerase - Telomerase - Telomerase + No division Finite division Potentially unlimited cell division AGING Dyskeratosis congenita
Aging, Cancer, and p53 Ferbeyre, G & Lowe, SW Nature 415: 26-7 (2002).
Interactions between p53/p21 and p16/Rb 2012 Cell Proliferation Group | http://cellpro.csc.mrc.ac.uk
Q: Which one of the following statements most accurately describes immune senescence? Q: Which one of the following statements most accurately describes immune senescence? It is associated with altered production of inflammatory cytokines. There is an increase in T and B cell diversity with age. It is similar in humans and mice. T memory cells decrease and T naïve cells increase with age. With aging, the response to new antigens remains intact.
Immune Senescence Immune Senescence (Perturbation of adaptive immune system with age) • Altered/diminished immune responsiveness – Decreased response to new antigens – Decreased vaccine efficiency (e.g., influenza) Compromised imm ne s r eillance (?) – Compromised immune surveillance (?) • Altered immune system physiology – Thymic involution – Decreased production of lymphocytes p y p y – Inversion in proportional representation of memory vs naïve cells (T memory cells increase and T naïve cells decrease with age) • Altered immunoregulation Increase in autoimmune syndromes (SLE RA SS others) – Increase in autoimmune syndromes (SLE, RA, SS, others) – Oligoclonal expansion of T- and B-cells (decrease in diversity with age) – Monoclonal gammopathies
Biology of Aging: An Overview • General Concepts Th i f A i • Theories of Aging • Aging at the Cellular and Molecular Level Level • Interventions in the Aging Process
Interventions in the Aging Interventions in the Aging Process • Cell-based therapies • Hormonal therapies Hormonal therapies • Genetic manipulations Di h i • Dietary therapies • Other: hypothermia, exercise
Dietary Therapies • Caloric Restriction – Extends average and maximum life spans by Extends average and maximum life spans by 30-40% if initiated in early adulthood, and by 20% if started in early middle age – Usually 30-60% reduction in calories with adequate content of essential nutrients – Effect preserved in a variety of species, including rodents, fish, flies, and worms
Effect of Dietary Restriction on Effect of Dietary Restriction on Life Span  Ad libitum  85 kcal/wk 100  50 kcal/wk  40 kcal/wk 75 50 25 25 0 Age (mo.) 0 0 10 20 30 40 50 60 Weindruch, R & Sohal, RS NEJM 337: 986-94 (1997).
Caloric Restriction in Non-human Primates A&B, 27 year old control; C&D, 27 year old CR
Caloric Restriction in Non-human Primates • Altered Growth, Development or • Improved Health – Lower weight Metabolism – Lower body temperatures – Less abdominal fat temperatures – Later sexual development p – Later skeletal maturation
Caloric Restriction in Non-human Primates • Reduced Risk for Age- related Diseases G t i li iti it • Effects in Rodents but Still under Investigation in Monkeys – Greater insulin sensitivity – Lower fasting insulin and glucose levels Monkeys – Later onset of age-related diseases (including cancer) – Lower cholesterol and triglyceride levels – Higher HDL levels – Longer average life span – Longer maximum life span – Lower IGF-I levels – Slower decline in DHEAS
Caloric Restriction in Non-human Primates
Caloric Restriction in Non-human Primates
Caloric Restriction in Humans • Okinawans Bi h 2 P j t • Biosphere 2 Project • Short-term studies in humans humans
Caloric Restriction in Humans Common to both CR nonhuman primates & long-lived Lower levels of plasma insulin Lower body temperature Maintenance of higher plasma 25% CR in humans x 6 months males Maintenance of higher plasma DHEA levels Roth, GS er al. Science 305:1423-6 (2004)
D Prototype Caloric-Restriction Mimetic D Lane, MA et al. Scientific Am. Aug 2002, 37-41.
Sirtuins (protein deacetylases): Sirtuins (protein deacetylases): mediators of caloric restriction ?
Resveratrol, a sirtuin activator, improves health and i l f i hi h l i di survival of mice on a high-calorie diet Baur, JA et al. Nature 444:337-42 (2006)
Effects of resveratrol • Extends lifespan of diverse lower species: S C i i • Changes parameters associated with longer lifespan: – S. Cerevisiae – C. elegans – D. melanogaster lifespan: – Increased insulin sensitivity D. melanogaster – Reduced IGF-I levels – Increased mitochondrial number mitochondrial number – Improved motor function
Dietary Therapies Dietary Therapies • Antioxidant supplementation D i ifi l h di i lif – Does not significantly change median or maximum life span – Except for vitamin E (and possibly vitamin C) being Except for vitamin E (and possibly vitamin C) being able to lower lipid oxidative damage, no evidence to support reduction in oxidative damage in humans d i h l d i i i ( – A compound with catalase and SOD activities (EUK- 134) extends longevity in nematodes – Foods with a high oxygen radical absorbance capacity Foods with a high oxygen radical absorbance capacity (ORAC) may be more protective than other antioxidant preparations – Antioxidants may help reduce the incidence of ARMD Butler, RN et al. J. Gerontol. 57A: B333-8 (2002).
Pharmaceuticals that have Pharmaceuticals that have potential to extend life span • National Institute of Aging has organized a multi-site study of in genetically heterogenous mice • Of the agents being tested aspirin and • Of the agents being tested, aspirin and nordihydroguaiaretic acid have been found to lead to significant increases in life span in males R i l d t i i i l it i • Rapamycin leads to an increase in maximum longevity in both males and females • Other compounds currently being tested as part of this initiative can be found at http://www.nia.nih.gov/ResearchInformation/ScientificRes ources/CompoundsInTesting.htm.
Rapam cin e tends lifespan Rapamycin extends lifespan Rapamycin: -- extended median and maximal lifespan of both male and female mice -- led to an increase in lifespan of 14% for females and 9% for males -- reproducible extended life span at three independent test sites in genetically heterogeneous mice heterogeneous mice -- did not affect disease patterns compared to control mice Harrison DE et al., Nature 2009
Other dietary manipulations that Other dietary manipulations that extend maximum life span • Low-methionine diets • Brief, but early nutritional deprivation Strong, R et all, Aging Cell (2009) Sun, L et al., J. Gerontol. (2009)

More Related Content

PPT
Gems 2006.ppt
byssuser3fe82a
 
PDF
THE BIOLOGY OF AGING cohen_bonkowski_0410.pdf
byMurilloGomes9
 
PDF
The Biology Of Human Longevity Inflammation Nutrition And Aging In The Evolut...
bymanokasmmy
 
PPTX
Introduction to gerontology
bySafaa Ali
 
PPT
Human Longevity by Justin Miller
byJustin2226
 
PPTX
Ageing and its relationship with longevity genes
byNazish_Nehal
 
PDF
Evans ageing 2010
bytcha163
 
PDF
Longevity set 4 fall_2013 (1)
byStephanie Martínez
 
Gems 2006.ppt
byssuser3fe82a
 
THE BIOLOGY OF AGING cohen_bonkowski_0410.pdf
byMurilloGomes9
 
The Biology Of Human Longevity Inflammation Nutrition And Aging In The Evolut...
bymanokasmmy
 
Introduction to gerontology
bySafaa Ali
 
Human Longevity by Justin Miller
byJustin2226
 
Ageing and its relationship with longevity genes
byNazish_Nehal
 
Evans ageing 2010
bytcha163
 
Longevity set 4 fall_2013 (1)
byStephanie Martínez
 

Similar to ageing ppt.pdf

PPT
Aging- the biology of senescence
byUniversity of Mumbai
 
PPTX
Theories of Aging - Part 1 in medicine and health sciences
byJackTan88
 
PPTX
Aging
byHussan Sheikh
 
PPTX
biology of ageing
byawan867
 
PPTX
Biological theories of aging
bydoaamohamed96
 
PDF
biologyofageing-200410161806.pdf
byRisdaArba1
 
PPTX
The pathology of aging- aetiology of aging .pptx
byakpamajaneabasiono
 
PPTX
Aging :- Topic for the medical Student.pptx
byvishwajitVishuthegre
 
PPT
Biology of Aging
byMuhammadasif909
 
PPTX
Aging and animal biotechnology
byiqraakbar8
 
PPTX
The Art and Science of Aging Well
byHawaiiNaturopathic
 
PDF
Maximum Life Span 1st Edition Roy L Walford
bydonepenar
 
PPTX
Physiology of aging presentation ppt form
byislamkhan34
 
PPTX
Geriatrics_(0).pptxxvvbbbbbbbnnnnnnnnnnk
byAbdirahmanIbrahimkad
 
PPTX
Reading&Writing C1.2 Unit 8.pptx
byKitPhanAnh2
 
PPTX
Theories of aging
bytanvi Pathania
 
DOCX
Aging and model of aging
byBahauddin Zakariya University lahore
 
PPTX
Modul Fisiologi Aging Juni 2020.pptx
byNurrahmanitaAziza1
 
PDF
Nrf2: A Guardian of Healthspan and Gatekeeper of Species Longevity
byLifeVantage
 
DOCX
Controversy 2Why Do Our Bodies Grow OldWhy Do Our Bodie.docx
bydonnajames55
 
Aging- the biology of senescence
byUniversity of Mumbai
 
Theories of Aging - Part 1 in medicine and health sciences
byJackTan88
 
Aging
byHussan Sheikh
 
biology of ageing
byawan867
 
Biological theories of aging
bydoaamohamed96
 
biologyofageing-200410161806.pdf
byRisdaArba1
 
The pathology of aging- aetiology of aging .pptx
byakpamajaneabasiono
 
Aging :- Topic for the medical Student.pptx
byvishwajitVishuthegre
 
Biology of Aging
byMuhammadasif909
 
Aging and animal biotechnology
byiqraakbar8
 
The Art and Science of Aging Well
byHawaiiNaturopathic
 
Maximum Life Span 1st Edition Roy L Walford
bydonepenar
 
Physiology of aging presentation ppt form
byislamkhan34
 
Geriatrics_(0).pptxxvvbbbbbbbnnnnnnnnnnk
byAbdirahmanIbrahimkad
 
Reading&Writing C1.2 Unit 8.pptx
byKitPhanAnh2
 
Theories of aging
bytanvi Pathania
 
Aging and model of aging
byBahauddin Zakariya University lahore
 
Modul Fisiologi Aging Juni 2020.pptx
byNurrahmanitaAziza1
 
Nrf2: A Guardian of Healthspan and Gatekeeper of Species Longevity
byLifeVantage
 
Controversy 2Why Do Our Bodies Grow OldWhy Do Our Bodie.docx
bydonnajames55
 

More from ssuser880f82

PDF
Transcription in prokaryotes and eukaryotes.pdf
byssuser880f82
 
PDF
Drosophila development.pdf
byssuser880f82
 
PPTX
module 4.pptx
byssuser880f82
 
PPT
dna-cloning- transformation.ppt
byssuser880f82
 
PDF
4.10.19_Amphibian_Metamorphosis.pdf
byssuser880f82
 
PPT
circulatory system mammals.ppt
byssuser880f82
 
PPTX
gastrulation.pptx
byssuser880f82
 
PPT
msc blotting 2d electro and isoelectric focussing.ppt
byssuser880f82
 
PPT
The Human Excretory System.ppt
byssuser880f82
 
PPT
electrophoresis.ppt
byssuser880f82
 
PPTX
TDS in Turtles.pptx
byssuser880f82
 
PPT
microbes
byssuser880f82
 
PPT
transgenic_plants.ppt
byssuser880f82
 
Transcription in prokaryotes and eukaryotes.pdf
byssuser880f82
 
Drosophila development.pdf
byssuser880f82
 
module 4.pptx
byssuser880f82
 
dna-cloning- transformation.ppt
byssuser880f82
 
4.10.19_Amphibian_Metamorphosis.pdf
byssuser880f82
 
circulatory system mammals.ppt
byssuser880f82
 
gastrulation.pptx
byssuser880f82
 
msc blotting 2d electro and isoelectric focussing.ppt
byssuser880f82
 
The Human Excretory System.ppt
byssuser880f82
 
electrophoresis.ppt
byssuser880f82
 
TDS in Turtles.pptx
byssuser880f82
 
microbes
byssuser880f82
 
transgenic_plants.ppt
byssuser880f82
 

Recently uploaded

PPTX
Aplastic_Anaemia_PA17.1_Presentation.pptx
byDibyajyoti Prusty
 
PDF
Fever & Fragment Uncovering the Plague in The Waste Land
byNidhi Pandya
 
PDF
Plant Respiration.pdf Remedial Biology Unit-5 B.Pharm 1st Year
bySaurabh Dubey
 
PPTX
What is Epiphany? A Visual introduction to this amazing liturgical season
bySteve Thomason
 
PPTX
1. Importance, scope and constraints of vegetable and spice crop production i...
byUmeshTimilsina1
 
PPTX
CHAPTER NO. 05 BIOLOGICAL SOURCE,CHEMICAL CONSTITUENTS AND THERAPEUTIC EFFICA...
byGanu Gavade
 
PPTX
L5 DRG Pulsed Radiofrequency ablation.pptx
bySandeep Margan
 
PPTX
Cultivation Practice of Brinjal in Nepal.pptx
byUmeshTimilsina1
 
PPTX
Haemolytic_Anaemia_UG_MBBS_Haemolysis_haemolysis
byDibyajyoti Prusty
 
PPTX
4. Nursery raising of vegetable crops.pptx
byUmeshTimilsina1
 
PDF
Digital_Empathy_Toolkit_Netiquette_and_Responsible_Communication
byNidhi Pandya
 
PDF
India Cybercrime Threats & Response 2025: Digital Arrests, 1930 Helpline & Ze...
bySanjay Rathod
 
PDF
Teaching and Learning (BD1TL) - B.Ed TNTEU
byDr Raja Mohammed T
 
PDF
• Reinforcing the Human Firewall: Moving From Awareness to Applied Skill
byAdityarajsinh Gohil
 
PDF
ADIEU, BRIGITTE BARDOT - THE ACTRESS WHO CHANGED THE WORLD.pdf
byMilanStankovic19
 
PPTX
Cultivation practice of Root vegetables.pptx
byUmeshTimilsina1
 
PPTX
Cultivation practice of Cucumber, Pumpkin and summer squash in Nepal.pptx
byUmeshTimilsina1
 
PPTX
CHAPTER 4. Size Reduction, Size Separation, Mixing, Filtration, Drying, Extra...
bySharibJamal
 
PPTX
Non aqueous titration First Year B. Pharm.pptx
byMs. Ashatai Patil
 
PPTX
What are the Custom lot_serial number in Odoo 19
byCeline George
 
Aplastic_Anaemia_PA17.1_Presentation.pptx
byDibyajyoti Prusty
 
Fever & Fragment Uncovering the Plague in The Waste Land
byNidhi Pandya
 
Plant Respiration.pdf Remedial Biology Unit-5 B.Pharm 1st Year
bySaurabh Dubey
 
What is Epiphany? A Visual introduction to this amazing liturgical season
bySteve Thomason
 
1. Importance, scope and constraints of vegetable and spice crop production i...
byUmeshTimilsina1
 
CHAPTER NO. 05 BIOLOGICAL SOURCE,CHEMICAL CONSTITUENTS AND THERAPEUTIC EFFICA...
byGanu Gavade
 
L5 DRG Pulsed Radiofrequency ablation.pptx
bySandeep Margan
 
Cultivation Practice of Brinjal in Nepal.pptx
byUmeshTimilsina1
 
Haemolytic_Anaemia_UG_MBBS_Haemolysis_haemolysis
byDibyajyoti Prusty
 
4. Nursery raising of vegetable crops.pptx
byUmeshTimilsina1
 
Digital_Empathy_Toolkit_Netiquette_and_Responsible_Communication
byNidhi Pandya
 
India Cybercrime Threats & Response 2025: Digital Arrests, 1930 Helpline & Ze...
bySanjay Rathod
 
Teaching and Learning (BD1TL) - B.Ed TNTEU
byDr Raja Mohammed T
 
• Reinforcing the Human Firewall: Moving From Awareness to Applied Skill
byAdityarajsinh Gohil
 
ADIEU, BRIGITTE BARDOT - THE ACTRESS WHO CHANGED THE WORLD.pdf
byMilanStankovic19
 
Cultivation practice of Root vegetables.pptx
byUmeshTimilsina1
 
Cultivation practice of Cucumber, Pumpkin and summer squash in Nepal.pptx
byUmeshTimilsina1
 
CHAPTER 4. Size Reduction, Size Separation, Mixing, Filtration, Drying, Extra...
bySharibJamal
 
Non aqueous titration First Year B. Pharm.pptx
byMs. Ashatai Patil
 
What are the Custom lot_serial number in Odoo 19
byCeline George
 

ageing ppt.pdf

  • 1.
    The Biology ofAging: An Overview Robert J. Pignolo, M.D., Ph.D. Assistant Professor of Medicine Division of Geriatric Medicine Fellow, Institute on Aging
  • 2.
    Biology of Aging:An Overview • General Concepts Th i f A i • Theories of Aging • Aging at the Cellular and Molecular Level Level • Interventions in the Aging Process
  • 3.
    Biology of Aging:An Overview • General Concepts Th i f A i • Theories of Aging • Aging at the Cellular and Molecular Level Level • Interventions in the Aging Process
  • 4.
    Aging v. Senescence BeneficialNeutral Deleterious Beneficial Neutral Deleterious
  • 5.
    Universality of Aging •No evidence that prokaryotes undergo senescence • Populations of single-celled eukaryotic organisms are immortal organisms are immortal • In multicellular organisms, senescence occurs in those that undergo somatic cell occurs in those that undergo somatic cell differentiation Masoro, E in Handbook of Physiology, Aging, Section 11:3-21 (1995).
  • 6.
    Rates of Senescence •RAPID: occurs abruptly after maturation (e.g. nematodes, flies) or soon after reproduction (e.g., annual plants, Pacific salmon) • GRADUAL: slow but persistent deterioration after i i ll l l l maturation in all placental mammals • NEGLIGIBLE: no clear evidence for t t ti l i i t lit t ( postmaturational increases in mortality rate (e.g., clams, trees, fish, reptiles) Finch, CE in Longevity, Senescence, and the Genome (1994).
  • 7.
    Q: Which ofthe following is true with regard to primary aging processes? They are deteriorative changes over time in the relative absence of disease or injury. Protection against premature death underlies survival increases that would otherwise be reduced secondary to primary aging processes. They do not influence maximum life span. They are not thought to be the underlying cause of senescence across species.
  • 8.
    Primary Aging Processes •Deteriorative changes over time in the relative absence of disease or injury j y • Influence maximum life span • Thought to be the underlying cause of • Thought to be the underlying cause of senescence across species
  • 9.
    Primary aging processesoccur in the absence of disease Bill Collins World’s Fastest 50 Year Old World Records: 5,000 M Run 450 d (m/min) 250 300 350 400 Men Women Speed 50 100 150 200 Age (yr) 20 40 60 80 100 Age 17 Age 52
  • 10.
    Median Length ofLife • Age at which there are as many individuals with shorter life spans as there are with p longer ones • Protection from premature death underlie Protection from premature death underlie survival increases • Thought NOT to reflect primary aging • Thought NOT to reflect primary aging processes
  • 11.
    Maximum Life Span •Age of the longest-lived survivors of a cohort or population p p • For humans, operationally considered to be the oldest age reached by 1 in 100 million the oldest age reached by 1 in 100 million people • Considered to be inversely proportional to • Considered to be inversely proportional to the rate of aging of a population
  • 12.
    Q: All ofthe following resulted in a dramatic increase in average life span in the early 1900s except: Sanitation Immunization Immunization Better nutrition Antibiotics Antibiotics
  • 13.
    Human Survivorship throughHistory Pignolo, RJ & Forciea, MA, in Geriatric Secrets, pp 7-13 (2004)
  • 14.
    Life Expectancy Listby the United N ti (2005 2010) Nations (2005-2010) Rank Country Life expectancy at birth (years) Life expectancy at birth (years) Life expectancy at birth (years) Overall Male Female 1 Japan 82.6 78.0 86.1 2 Hong Hong 82.2 79.4 85.1 3 Iceland 81.8 80.2 83.3 4 Switzerland 81.7 79.0 84.2 5 Australia 81.2 78.9 83.6 6 Spain 80.9 77.7 84.2 7 Sweden 80.9 78.7 83.0 8 Israel 80.7 78.5 82.8 9 Macau 80.7 78.5 82.8 10 France (metro) 80.7 77.1 84.1 11 Canada 80.7 78.3 82.9 12 Italy 80.5 77.5 83.5 36 United States 78.3 75.6 80.8
  • 15.
  • 16.
  • 17.
    Longest-lived Humans J Cl t (F ) Ch i ti M t Jeanne Calment (France) Lived to age 122 Christian Mortensen (Danish-American) Lived to age 115 Robine, J-M & Allard, M, Science 279: 1834-5 (1998). Deianna, L et al. JAGS 50: 2098-9 (2002).
  • 18.
    Q: Examples oflong-lived human populations point to which of the following pro-longevity factor(s): Q: Examples of long lived human populations point to which of the following pro longevity factor(s): Genetic pre-disposition Dietary practices Spirituality Conformity to beneficial health practices All of the above
  • 19.
    The places wherepeople live the longest • Okinawa, Japan • Ovodda, Sardinia , (Italy) • Loma Lida, CA (USA)
  • 20.
    Keys to longevity-Okinowa •“hara haci bu” • Rainbow diet • Diet: soy > fish, meat, eggs, dairy • BMI 20.4 • ~1200 cal diet • DHEA levels decline more slowly
  • 21.
    Keys to longevity-Ovodda, Sardinia • As many men live to 100 as women • Sardinians who emigrated • Sardinians who emigrated at 20, 30 or 40 years of age still manage to reach 100 100 • Descended from only a few original settlers – i l t d i t b di isolated, interbreeding • G6PD deficiency, other genetic traits?
  • 22.
    Keys to longevity-Loma Linda, CA • Seventh Day Adventists • Members live 5-10 years longer than fellow citizens • No drinking or smoking • Many adhere to a vegetarian diet the church advises • Spiritual life • Regular churchgoers – of whatever faith - live longer • Significantly lower levels of stress hormones
  • 23.
    Keys to longevity “Hl ld li if “How long would you live if you were a Sardinian 7th Day Adventist who moved to Oki t 20 f ?” Okinawa at 20 years of age?”
  • 24.
    Broken Limits toLife Expectancy Broken Limits to Life Expectancy Female life-expectancy in Japan has risen for 160 years at a steady 160 years at a steady pace of almost 3 m/yr! Oeppen & Vaupel Science 296: 1029-31 (2002)
  • 25.
    Compression of Morbidity Fries,JF Ann Int Med 139:455-9 (2003)
  • 26.
    Q: Which istrue regarding morbidity with increased life span as reflected by disability trends? Morbidity increases with life extension. Morbidity remains the same with increased life span. Morbidity is compressed.
  • 27.
    Q: Which ofthe following is true regarding the onset of age-related disease in centenarians? Age-related disease is delayed by almost one decade. Age-related disease occurs at about the same time in centenarians as in individuals with Age related disease occurs at about the same time in centenarians as in individuals with average life expectancy. Age-related disease does not occur in centenarians. Age-related disease may occur at about the same time as in individuals with average life Age-related disease may occur at about the same time as in individuals with average life spans, may be delayed or even absent in centenarians.
  • 28.
    Who are centenarians? Whoare centenarians? Survivors D l Delayers Escapers
  • 29.
    ____________________________________________________________________________ Characteristics of AgingExamples ____________________________________________________________________________ Increased mortality after maturation Survival curves showing exponential Increased mortality after maturation Survival curves showing exponential increase in mortality with age Changes in biochemical composition of tissues Increases in lipofuscin or age pigment Increased cross-linking in extracellular g matrix molecules such as collagen Progressive, deteriorative physiologic changes Declines in glomerular filtration rate, maximal heart rate, vital capacity Decreased ability to adaptively respond to Decreased "first past" hepatic metabolism environmental changes Blunted maximal cardiac responses to exercise Increasing incidence of many diseases Ischemic heart disease, type II diabetes, osteoporosis, Alzheimer's disease ____________________________________________________________________________ Cristofalo, VJ, Gerhard, GS & Pignolo, RJ Surg. Clin. N. Am. 74: 1-21 (1994).
  • 30.
    ____________________________________________________________________________ Characteristics of AgingE ceptions Characteristics of Aging Exceptions ____________________________________________________________________________ Increased mortality after maturation Human age-specific mortality rates do not continue to increase exponentially at very advanced ages advanced ages Changes in biochemical composition of tissues Changes are quite heterogeneous from organ to organ within a specific individual and also from individual to individual ("usual" and "successful" aging) Progressive, deteriorative physiologic changes " " Decreased ability to adaptively respond to " " environmental changes Increasing incidence of many diseases Elimination of atherosclerosis and cancer as causes of death would only add about ten years to average life span and would not affect maximum life span potential ____________________________________________________________________________
  • 32.
    Biology of Aging:An Overview • General Concepts Th i f A i • Theories of Aging • Aging at the Cellular and Molecular Level Level • Interventions in the Aging Process
  • 33.
    Stochastic or Random Error Theories Genetic/ Developmental Thi Theories Evolutionary Theory Theories of Aging Theories of Aging
  • 34.
    Cumulative Oxidative Damageduring A i Aging Weindruch, R & Sohal, RS NEJM 337: 986-94 (1997).
  • 35.
    Q: All ofthe following evidence supports a genetic basis for longevity, except: Common polymorphisms in the APOE gene have a modest effect on life span. There is high conservation of maximum life span seen between species There is high conservation of maximum life span seen between species . There are examples of exceptional longevity within families. Twin studies demonstrate that genetic differences likely account for about 50% of the Twin studies demonstrate that genetic differences likely account for about 50% of the variance in adult human life span.
  • 36.
    Genetic Basis ofAging Theories Hi h ti f i lif • High conservation of maximum life span between species • Similarity of attained age between monozygotic twins compared to dizygotic twins or nontwin siblings • Examples of exceptional longevity within p p g y families • Subsets of aging features in human genetic Subsets of aging features in human genetic syndromes of premature aging
  • 37.
    Most commonly describedhuman segmental progeroid syndromes. Syndrome Incidence (per live Inheritance Mean life- Progeroid features Genome maintenance y (p birth) span (years) g defect Hutchinson- Gilford <1/1,000,000 Unknown ~13 Alopecia, sclerosis, wrinkling, soft tissue, cachexia, arteriosclerosis, diminished fat Laminin Werner <1/100 000 Autosomal 50 Alopecia, osteoporosis, malignancies, arteriosclerosis diabetes cataracts DNA helicase (RecQ like) Werner <1/100,000 recessive ~50 arteriosclerosis, diabetes, cataracts, telangiectasia, skin atrophy, graying of hair (RecQ-like), exonuclease Rothmund- Thomson <1/100,000 Autosomal recessive Normal ? Alopecia, malignancies, poikiloderma, cataracts, osteoporosis, graying of hair DNA helicase (RecQ-like) Cockayne ~1/100,000 Autosomal recessive ~20 Thin hair, cachexia, retinal degeneration, hearing loss, neurodegeneration (cerebellar ataxia), cataracts Transcription- coupled DNA repair cataracts repair Trichothiodys trophy <1/100,000 Autosomal recessive ~10 Cachexia, osteoporosis, cataracts, fragile hair, neurodegeneration (cerebellar ataxia) DNA repair, basal transcription Ataxia telangiectasia ~1/60,000 Autosomal recessive ~20 Skin atrophy/sclerosis, telangiectasia, immunodeficiencies, malignancies, graying of hair, poikiloderma, neurodegeneration DNA damage signaling protein kinase (cerebellar ataxia) protein kinase Down ~1/1,000 De novo ~60 Cataracts, graying of hair, alopecia, diminished subcutaneous fat, vision loss, neurodegeneration (Alzheimer-like), thyroid dysfunction Trisomy Adapted from Hasty, P et al. Science 299: 1355-59 (2003).
  • 38.
    Evolutionary Theory • Riskof mortality increases with time after reproduction • Genes that confer early benefits on reproductive fitness are selected, even if they cause deleterious ff l i lif effects later in life • No selective pressure against genes that confer ti ff t l t i lif negative effects later in life • Strong pressure to retain genes that diminish l bilit i d ld lik vulnerability in young and old alike
  • 39.
    Biology of Aging:An Overview • General Concepts Th i f A i • Theories of Aging • Aging at the Cellular and Molecular Level Level • Interventions in the Aging Process
  • 40.
    Replication Potential ofNormal Replication Potential of Normal Human Cells Soma Germ Line Post-mitotic cells Quiescent Stem cells Primative germ cells (e.g., spermatogonia) Post mitotic cells (e.g., neurons) Quiescent, Replication-competent Somatic cells (e.g., fibroblasts) Stem cells (e.g., early hematopoietic precurcurs, gut-lining cells) No division Finite division Potentially unlimited cell division No division Finite division Potentially unlimited cell division
  • 41.
    Q: Some characteristicsassociated with replicative senescence include all of the following except: Q: So e c a ac e s cs assoc a ed ep ca e se esce ce c ude a o e o o g e cept Apoptosis resistance Finite replicative life span Altered pattern of gene expression Promotion of intrinsic aging in all cell types Essentially irreversible growth arrest.
  • 42.
    Cellular (Replicative) Senescence Stagesin the in vitro life history of normal human diploid fibroblasts ll Number T r a n s f o r m a t i o n III Cumulative Cel II III IV Cell Aging C I V g g Adapted from Cristofalo, V.J. and Pignolo, R.J. Handbook of the Physiology of Aging, Oxford University Press, 1995.
  • 43.
    Telomere Shortening with TelomereShortening with Cellular Aging Harley, CB et al. , Nature 345: 458-60 (1990).
  • 44.
  • 45.
    Replication Potential ofNormal Replication Potential of Normal Human Cells Soma Germ Line Post-mitotic cells Quiescent Stem cells Primative germ cells (e.g., spermatogonia) Post mitotic cells (e.g., neurons) Quiescent, Replication-competent Somatic cells (e.g., fibroblasts) Stem cells (e.g., early hematopoietic precurcurs, gut-lining cells) T l Telomerase + No division Finite division Potentially unlimited cell division Telomerase - Telomerase - Telomerase + No division Finite division Potentially unlimited cell division
  • 46.
    Aging in Telomerase-deficientmice • Age-dependent telomere shortening G i i bili • Genomic instability • Shortened life span • Reduced capacity to respond to stressors I d • Increased spontaneous malignancies Villi t f ll • Villi atropy of small intestine Rudolph, KL et al. Cell 96: 701-12 (1999).
  • 47.
    Aging in Telomerase-deficientHumans Marciniak, R & Guarente, L Nature 413: 370-3 (2001).
  • 48.
    Replication Potential ofNormal Replication Potential of Normal Human Cells Soma Germ Line Post-mitotic cells Quiescent Stem cells Primative germ cells (e.g., spermatogonia) Post mitotic cells (e.g., neurons) Quiescent, Replication-competent Somatic cells (e.g., fibroblasts) Stem cells (e.g., early hematopoietic precurcurs, gut-lining cells) T l Telomerase + No division Finite division Potentially unlimited cell division Telomerase - Telomerase - Telomerase + No division Finite division Potentially unlimited cell division AGING
  • 49.
    Replication Potential ofNormal Replication Potential of Normal Human Cells Soma Germ Line Post-mitotic cells Quiescent Stem cells Primative germ cells (e.g., spermatogonia) Post mitotic cells (e.g., neurons) Quiescent, Replication-competent Somatic cells (e.g., fibroblasts) Stem cells (e.g., early hematopoietic precurcurs, gut-lining cells) T l Telomerase + No division Finite division Potentially unlimited cell division Telomerase - Telomerase - Telomerase + No division Finite division Potentially unlimited cell division AGING Dyskeratosis congenita
  • 50.
    Aging, Cancer, andp53 Ferbeyre, G & Lowe, SW Nature 415: 26-7 (2002).
  • 51.
    Interactions between p53/p21and p16/Rb 2012 Cell Proliferation Group | http://cellpro.csc.mrc.ac.uk
  • 52.
    Q: Which oneof the following statements most accurately describes immune senescence? Q: Which one of the following statements most accurately describes immune senescence? It is associated with altered production of inflammatory cytokines. There is an increase in T and B cell diversity with age. It is similar in humans and mice. T memory cells decrease and T naïve cells increase with age. With aging, the response to new antigens remains intact.
  • 53.
    Immune Senescence Immune Senescence (Perturbationof adaptive immune system with age) • Altered/diminished immune responsiveness – Decreased response to new antigens – Decreased vaccine efficiency (e.g., influenza) Compromised imm ne s r eillance (?) – Compromised immune surveillance (?) • Altered immune system physiology – Thymic involution – Decreased production of lymphocytes p y p y – Inversion in proportional representation of memory vs naïve cells (T memory cells increase and T naïve cells decrease with age) • Altered immunoregulation Increase in autoimmune syndromes (SLE RA SS others) – Increase in autoimmune syndromes (SLE, RA, SS, others) – Oligoclonal expansion of T- and B-cells (decrease in diversity with age) – Monoclonal gammopathies
  • 54.
    Biology of Aging:An Overview • General Concepts Th i f A i • Theories of Aging • Aging at the Cellular and Molecular Level Level • Interventions in the Aging Process
  • 55.
    Interventions in theAging Interventions in the Aging Process • Cell-based therapies • Hormonal therapies Hormonal therapies • Genetic manipulations Di h i • Dietary therapies • Other: hypothermia, exercise
  • 57.
    Dietary Therapies • CaloricRestriction – Extends average and maximum life spans by Extends average and maximum life spans by 30-40% if initiated in early adulthood, and by 20% if started in early middle age – Usually 30-60% reduction in calories with adequate content of essential nutrients – Effect preserved in a variety of species, including rodents, fish, flies, and worms
  • 58.
    Effect of DietaryRestriction on Effect of Dietary Restriction on Life Span  Ad libitum  85 kcal/wk 100  50 kcal/wk  40 kcal/wk 75 50 25 25 0 Age (mo.) 0 0 10 20 30 40 50 60 Weindruch, R & Sohal, RS NEJM 337: 986-94 (1997).
  • 59.
    Caloric Restriction inNon-human Primates A&B, 27 year old control; C&D, 27 year old CR
  • 60.
    Caloric Restriction inNon-human Primates • Altered Growth, Development or • Improved Health – Lower weight Metabolism – Lower body temperatures – Less abdominal fat temperatures – Later sexual development p – Later skeletal maturation
  • 61.
    Caloric Restriction inNon-human Primates • Reduced Risk for Age- related Diseases G t i li iti it • Effects in Rodents but Still under Investigation in Monkeys – Greater insulin sensitivity – Lower fasting insulin and glucose levels Monkeys – Later onset of age-related diseases (including cancer) – Lower cholesterol and triglyceride levels – Higher HDL levels – Longer average life span – Longer maximum life span – Lower IGF-I levels – Slower decline in DHEAS
  • 62.
    Caloric Restriction inNon-human Primates
  • 63.
    Caloric Restriction inNon-human Primates
  • 64.
    Caloric Restriction inHumans • Okinawans Bi h 2 P j t • Biosphere 2 Project • Short-term studies in humans humans
  • 65.
    Caloric Restriction inHumans Common to both CR nonhuman primates & long-lived Lower levels of plasma insulin Lower body temperature Maintenance of higher plasma 25% CR in humans x 6 months males Maintenance of higher plasma DHEA levels Roth, GS er al. Science 305:1423-6 (2004)
  • 67.
    D Prototype Caloric-Restriction Mimetic D Lane,MA et al. Scientific Am. Aug 2002, 37-41.
  • 68.
    Sirtuins (protein deacetylases): Sirtuins(protein deacetylases): mediators of caloric restriction ?
  • 69.
    Resveratrol, a sirtuinactivator, improves health and i l f i hi h l i di survival of mice on a high-calorie diet Baur, JA et al. Nature 444:337-42 (2006)
  • 70.
    Effects of resveratrol •Extends lifespan of diverse lower species: S C i i • Changes parameters associated with longer lifespan: – S. Cerevisiae – C. elegans – D. melanogaster lifespan: – Increased insulin sensitivity D. melanogaster – Reduced IGF-I levels – Increased mitochondrial number mitochondrial number – Improved motor function
  • 71.
    Dietary Therapies Dietary Therapies •Antioxidant supplementation D i ifi l h di i lif – Does not significantly change median or maximum life span – Except for vitamin E (and possibly vitamin C) being Except for vitamin E (and possibly vitamin C) being able to lower lipid oxidative damage, no evidence to support reduction in oxidative damage in humans d i h l d i i i ( – A compound with catalase and SOD activities (EUK- 134) extends longevity in nematodes – Foods with a high oxygen radical absorbance capacity Foods with a high oxygen radical absorbance capacity (ORAC) may be more protective than other antioxidant preparations – Antioxidants may help reduce the incidence of ARMD Butler, RN et al. J. Gerontol. 57A: B333-8 (2002).
  • 72.
    Pharmaceuticals that have Pharmaceuticalsthat have potential to extend life span • National Institute of Aging has organized a multi-site study of in genetically heterogenous mice • Of the agents being tested aspirin and • Of the agents being tested, aspirin and nordihydroguaiaretic acid have been found to lead to significant increases in life span in males R i l d t i i i l it i • Rapamycin leads to an increase in maximum longevity in both males and females • Other compounds currently being tested as part of this initiative can be found at http://www.nia.nih.gov/ResearchInformation/ScientificRes ources/CompoundsInTesting.htm.
  • 73.
    Rapam cin etends lifespan Rapamycin extends lifespan Rapamycin: -- extended median and maximal lifespan of both male and female mice -- led to an increase in lifespan of 14% for females and 9% for males -- reproducible extended life span at three independent test sites in genetically heterogeneous mice heterogeneous mice -- did not affect disease patterns compared to control mice Harrison DE et al., Nature 2009
  • 74.
    Other dietary manipulationsthat Other dietary manipulations that extend maximum life span • Low-methionine diets • Brief, but early nutritional deprivation Strong, R et all, Aging Cell (2009) Sun, L et al., J. Gerontol. (2009)