Genetics of longevity and aging • Hiljar Sibul • 15.05.2007
This map shows the worldwide distribution of people over 65 years old.http://www.worldmapper.org/ In 2002 7% of the world population was over 65 years old.China has the largest elderly population (92 million) but this is only 7% of the Chinese population. Africa is home to only 6% of the world's population aged over 65.
World Population Ageing: 1950-2050 • Population ageing is unprecedented, without parallel in human history—and the twenty-first century will witness even more rapid ageing than did the century just past. • Population ageing is pervasive, a global phenomenon affecting every man, woman and child. • Population ageing is enduring: we will not return to the young populations that our ancestors knew. • Population ageing has profound implications for many facets of human life.
Definitions (Wikipedia) • Senescence (aging) - the combination of processes of deterioration which follow the period of development of an organism • Longevity is the length of a person's life (life expectancy). • Life expectancy is a statistical measure of the average length of survival of a living thing. • Maximum life span is a measure of the maximum number of years a member of a group has been observed to survive. . Maximum life span is contrasted to mean life span (average lifespan or life expectancy).
Demography: the prevalence of age-related frailty, disability and disease is rapidly increasing and will continue to increase. Clinical medicine: age is the single largest risk factor for a very wide range of diseases of current public health importance. Biomedical science: why is the aged cell (or organ) more vulnerable to pathology? Ageing - A Challenge of Our Time
We live, on average, about twice as long as we did 200 years ago. Life expectancy has increased by about 10 years in the last 50 years. 85 per cent of children born today can expect to reach their 65th birthday. Living Longer
What is the evidence for genetic influences on longevity? What kinds of genes affect longevity? How amenable is the ageing process to modification? Are the genetic determinants of longevity changing? Genetics of Longevity – Key Questions
Genetic Heritability of Human LifespanCournil & Kirkwood 2001 Twin Studies • McGue et al (1993) 0.22 • Herskind et al (1996) 0.25 • Ljungquist et al (1998) <0.33 Traditional Family Studies • Philippe (1978) 0-0.24 • Bocquet-Appel & Jakobi (1990) 0.10-0.30 • Mayer (1990) 0.10-0.33 • Gavrilova et al (1998) 0.18-0.58 • Cournil et al (2000) 0.27 Genes account for 25% of what determines longevity. Longevity has strong genetic basis – familial clustering – centenarian offsprings have reduced relative prevalence for heart disease – 56%, hypertension – 66%, diabetes – 59%. (Ann Int Med V139N5 pp 445-449)
It is remarkable, that after a seemingly miraculous feat of morphogenesis a complex metazoan should be unable to perform the much simpler task of merely maintaining what is already formed. Williams, G.C. (1957). Pleiotropy, natural selection, and the evolution of senescence. Evolution 11, 398-411 (Metazoans include everything from sponges and jellyfish to insects and vertebrates.) "Senescence has no function--it is the subversion of function.“ Alex Comfort
Biological Theoriesof Aging • Wear-and-Tear theory • The idea that changes associated with aging are the result of chance damage that accumulates over time. • Somatic Mutation Theory • This is the biological theory that aging results from damage to the genetic integrity of the body’s cells. • Error Accumulation Theory • This is the idea that aging results from chance events that gradually damage the genetic code. • Accumulative-Waste Theory • The biological theory of aging that points to a buildup of cells of waste products that presumably interferes with metabolism.
Biological TheoriesII • Autoimmune Theory • This is the idea that aging results from gradual decline in the body’s autoimmune system. • Aging-Clock Theory • The idea that aging results from a preprogrammed sequence, as in a clock, built into the operation of the nervous or endocrine system of the body. • Cross-Linkage Theory • This is the idea that aging results from accumulation of cross-linked compounds that interfere with normal cell function. • Free-Radical Theory • The idea that free radicals (unstable and highly reactive organic molecules) create damage that gives rise to symptoms we recognize as aging. • Cellular Theory • This is the view that aging can be explained largely by changes in structure and function taking place in the cells of an organism. • The disposable soma theory of senescence proposes that aging is the result of the accumulation of somatic damage with age resulting from insufficient somatic maintenance and repair. • Antagonistic pleiotropy theory - According to the antagonistic pleiotropy theory of ageing, natural selection has favoured genes conferring short-term benefits to the organism at the cost of deterioration in later life.
Aging and natural environment Animals rarely become senescent in natural environment – predation, disease, starvation, drought, accident. Gray squirrel – survival after 4 years 6-7%. That makes a claim that aging may be pre-programmed dubious. No need. Protected environment – zoo, lab – permits to reach maximum life span.
Causes of aging Multiple causes for senescence – mutation accumulation in nuclear and mitochondrial genome, abnormal modifications of proteins, damage by ROS (reactive oxygen species),defective immunity (loss or autoreactive), decline in muscle strenght, osteoporosis, osteoarthritis, inflammatory damages to tissues, hormone imbalance, epigenetic abnormalities, greatly increased incidence to tumours. Why do mammalian and bird species live as long as they do? The answer depends on the efficiency of cell, tissue, and organ maintenance in each species. Maintenance mechanisms are very extensive, and consume considerable resources.
Free radicals - where do they come from? • Eucaryotic cells continuously produce reactive oxygen intermediates (ROIs) as a side products of electron transfer. There are several major ROI species, including H2O2, superoxide and hydroxyl radicals. Abnormally high level of ROIs is refered to as oxidative stress. • This occurs frequently in cells exposed to UV light, X rays or H2O2. Under normal, physiological condition the cell is also dealing with free radicals coming from respiratory chain, peroxysoms, microsomes and enzymatic reaction including the ones catalyzed by oxygenases and reductases. The most dangerous among all ROI species is hydroxyl radical and it arises as a product of the reaction between superoxide and H2O2. The reaction is catalysed by Fe2+ and is named after the famous chemist as Fenton reaction. • Fe2+ / Fe3+ • O2_. + H2O2 ---------------------- > OH. + OH- + O2
Maintenance mechanisms 1. the multiple pathways of DNA repair, which are vital for the removal of spontaneous lesions in DNA; 2. the defenses against oxygen-free radicals, which include antioxidants and enzymes; 3. the removal of defective proteins by proteases; 4. protein repair, such as the renaturation of proteins by chaperones, and the enzymic reversal of oxidization of amino acids; 5. the accuracy of synthesis of macromolecules, which depends on proofreading mechanisms; 6. the immune response against pathogens and parasites; 7. the detoxification of harmful chemicals in the diet by the monooxygenase enzymes coded for by the P450 gene superfamily;
8. wound healing, blood clotting, and the healing of broken bones and torn ligaments; 9. physiological homeostasis, including temperature control; 10. the epigenetic stability of differentiated cells, and the defenses against neoplastic transformation; 11. apoptosis, which is the means of removing unwanted or damaged cells; 12. the storage of fat, to allow animals to survive in the absence of food; 13. grooming of fur or feathers, which removes external parasites, dirt, and debris. All these mechanisms depend on a large number of genes. For example, at least 1,000 genes are required for the immune system), and 150 genes for DNA repair
THE ALLOCATION OF RESOURCES • The energy and metabolic resources available to any animal must be divided between three fundamental features of life. • The first comprises basic metabolism, which includes biochemical synthesis; respiration; cell turnover; movement; feeding, digestion, and excretion. • The second is reproduction, which depends in mammals on the gonads, gametes, and sex; gestation and development; suckling; care of offspring, and growth to the adult. • The third is maintenance, namely all the 13 functions listed above.
Whereas basic metabolism is essential for all animals, the extent of investment in reproduction and maintenance can vary between species. • More investment in maintenance and less in reproduction results in an increase in life span. The evolved balance between the two depends on the life history strategy and ecological niche of the species. • long-lived species have more efficient maintenance mechanisms than short-lived species (e.g. defenses against ROS in a long-lived bird, the pigeon, are much more efficient than those in the short-lived rat, a mammal of similar size and metabolic rate. .
THE MODULATION OF AGING • It is very well known that calorie restriction in rodents substantially increases their life span, and it also greatly reduces their fecundity. • (mechanism highly uncertain) • When food is absent or limited, it would be disadvantageous for females to breed, and better to invest available resources in maintenance and survival. • When food becomes available, reproduction can then occur. • The overall effect with a variable or limited food supply is to increase the life span. • Mutations in genes that increase longevity (in so-called gerontogenes) are likely to have deleterious effects on the phenotype, such as loss of fertility. • Such animals would not compete with wild-type animals in a natural environment. • For example, there may be ways and means of reducing metabolic rate, or reducing temperature, or increasing sleep, all of which could conceivably increase longevity.
The rate of aging and maximum lifespan vary among species. These differences demonstrate the role of genetics in determining maximum life span ("rate of aging").
The records are: • for mice 4; • for dogs 29; • for cats 34; • for goldfish 49 • for horses, 62; • for elephants, 78; • for humans, 122.5 • The longest-lived vertebrates have been variously described as • tortoises (Galápagos tortoise) (193 years) • whales (Bowhead Whale) (about 210 years)
From the model organisms (e.g. S. cerevisiae, D. melanogaster, C. elegans), clear candidate genetic pathways and mechanisms underpinning ageing and longevity have emerged.
Some important aging genes(worm, human analogues mostly present) • age-1; daf-23; daf-2, daf-16, daf-18 - Insulin receptor aging pathway • Clk-1 - Mitochondrial protein involved in coenzyme Q synthesis (altered biological clock • Clk-2, clk-3 (altered biological clock) • Eat-2 - caloric restriction->life-extension • Spe-26 - reduced fertility/life-extension • WRN (Werner syndrome) DNA helicase, RecQ family (human) • Sir2 - NAD)-dependent histone deacetylase (deletions shorten life span)
How Sir2- silenced chromatin might promote longevity. In yeast, silencing in the rDNA represses recombination (genome instability) and thus extends life span. In general, silencing also prevents inappropriate gene expression, which may be relevant to the maintenance of differentiated cells in metazoans and the extension of life span. www.genesdev.org/cgi/content/full/14/9/1021
Life extension given by genotype - C. elegans Life extension (wt = 100%) • daf-2(e1370) clk-1(e2519) - 500% (DAF-2 is the insulin/IGF-1 like receptor in the worm) • age-1- 165% (phosphotidyl-inositol-3-OH-kinase (PI(3)K), a key biological mediator of cellular communication and signal transduction) • age-2(yw23) - 120% • daf-28(sa191) - 12-13% • eatgenes – 100-150% (caloric restriction) • sperm production mutant - 165% (trading off – fertility versus longevity)
Age-1 • In Caenorhabditis elegans, the switch to increased stress resistance to promote survival through periods of starvation is regulated by the DAF-16/FOXO transcription factor. • Reduction-of-function mutations in AGE-1, the C. elegans Class IA phosphoinositide 3-kinase (PI3K), increase lifespan and stress resistance in a daf-16 dependent manner. Class IA PI3Ks downregulate FOXOs by inducing their translocation to the cytoplasm.
Life extension for other organisms - D. melanogaster • Transgene Cu/Zn SOD and catalase - 34% • Transgene human SOD1 in adult motor neurons - 40% • methuselah - 35% - the gene (mth) has been proposed as having major effects on organismal stress response and longevity phenotype. Analysis of single nucleotide polymorphisms (SNPs) in D. melanogaster provided evidence for contemporary and spatially variable selection at the mth locus.
Life-span extension in methuselah. Male flies of the parental strain (white1118) and methuselah (homozygous for the P-element insertion) were maintained in a constant temperature, humidity, and 12/12 hour dark/light cycle environment. Flies were transferred to fresh food vials and scored for survival every 3 to 4 days. (A) Survival curve. The average life-spans for w1118 and mth were 57 and 77 days, respectively. The numbers of flies tested were 876 for w1118 and 783 for mth. (B) Mortality rate. Logarithm of mortality rate (the fraction of flies dying per day) is plotted against age. • Science Magazine > 30 October 1998 > Lin et al.,
Genetic Heritability of Human LifespanCournil & Kirkwood 2001 Twin Studies • McGue et al (1993) 0.22 • Herskind et al (1996) 0.25 • Ljungquist et al (1998) <0.33 Traditional Family Studies • Philippe (1978) 0-0.24 • Bocquet-Appel & Jakobi (1990) 0.10-0.30 • Mayer (1990) 0.10-0.33 • Gavrilova et al (1998) 0.18-0.58 • Cournil et al (2000) 0.27 Genes account for 25% of what determines longevity
Aspects of centenarian biology Comparison of centenarians with adults of various ages: Lower body mass index (BMI). Lower body fat. Lower plasma triglycerides. Lower oxidative stress levels. Higher insulin sensitivity (less susceptible to type II diabetes.) Higher plasma levels of active IGF-1. Barbieri et al., 2003, Paolisso et al., 1997. Absence of deleterious alleles of disease genes. Cancer, vascular disease, neurodegenerative disease, diabetes, etc.
Aspects of centenarian biology II • Some centenarians have long history of an age-related disease – unusual adaptive capacity or functional reserve? • Three profiles : • a) survivors – age-associated disease diagnosed before 80 yrs of age. (42%) • b) delayers - age-associated disease diagnosed at or after 80 yrs of age (45%) • c) escapers – attained their 100th birthday without diagnosis of any of the 10 common age-associated diseases • Different phenotypes, probably different genotypes? • Children of centenarians are unusuallu healthy.
Apolipoprotein E (ApoE) • Study of French centenarians. 338 cenenarians, controls aging 20-70. • 4 allele of ApoE, which promotes premature atherosclerosis, is significantly less frequent in centenarians than in controls (p<0.001) • Frequency of the 2 allele significantly increased (p<0.01). • Schachter et al., 1994 • ApoE2 protects against cardiovascular disease and Alzheimer’s disease.
Mitochondrial polymorphisms • Study of 321 very old subjects and 489 middle-aged controls from Finland and Japan • Three common inherited mitochondrial DNA polymorphisms (150T, 489C, and 10398G) promotes longevity. • Niemi et al., 2005 • Reason for the association? Unclear.
IL-10 promoter polymorphism • Hypothesis: Genetic variations in pro- or anti-inflammatory cytokines might influence successful ageing and longevity. IL-10 is an appropriate candidate because it exerts powerful inhibitory effects on pro-inflammatory function. • Study of 190 Italian centenarians (>99 years old, 159 women and 31 men) and in 260 <60 years old control subjects (99 women and 161 men). • Matched for geographical distribution, genotype frequencies. • -1082G homozygous genotype (associated with high IL-10 production) was increased in centenarian men (P < 0.025) but not in centenarian women. • Anti-inflammatory IL-6 and IFN-gamma gene polymorphisms associated with longevity in other studies. • Lio et al., 2002
Negative/mixed results • Sirtuin 1, SIRT1 (negative) • Microsomal Transfer Protein (mixed) • Cholesteryl ester transfer protein, CETP (mixed) • FOXO1A, INSR, IRS1, PIK3CB, PIK3CG, and PPARGC1A (negative) • Catalase (mixed) • ACE1 (mixed)
Insulin receptor (INSR) • INSR • Study of 122 Japanese semisupercentenarians (older than 105) with 122 healthy younger controls. • One INSR haplotype, which was comprised of 2 SNPs in linkage disequilibrium, was more frequent in semisupercentenarians than in younger controls. • Kojima et al., 2004
(PPAR)gamma-2 • Peroxisome proliferator-activated receptor (PPAR)gamma-2 is an important regulator of adipose tissue metabolism, insulin sensitivity and inflammatory response. • Study of 222 long-lived subjects and 250 aged subjects. • Long-lived men had an increased frequency of Pro/Ala genotype (20% vs 8.5%). • Subjects with Pro/Ala polymorphism had significantly lower BMI. • Barbieri et al., 2004
Genes influence longevity but there are multiple genes and the total genetic contribution is ca. 25%. Genetic determinants of longevity are principally those that affect cellular maintenance and repair, either directly or indirectly. Environmental factors (and chance) significantly modify gene actions. Present-day environments differ significantly from those in which the genetic determinants of longevity evolved. Conclusions
European 6th frame program - LifeSpan WP08 – genetic variation and life span
From the model organisms (e.g. S. cerevisiae, D. melanogaster, C. elegans), clear candidate genetic pathways and mechanisms underpinning ageing and longevity have emerged. The key objective of this work packages to determine whether, and if so, which candidate genes in model organisms also cause variation in longevity and ageing rate in human populations.
To achieve the objective we will use a candidate gene approach. In order to do this we will establish a database of the candidate genes, based on previous results in model organisms. • We estimate to have about 500 good candidate genes in this database with human SNP and haplotype information attached to it.
What should be done • SNP-based genome scans for association of genes/alleles and longevity • If lucky, we may find genes associated with slower aging as well as disease prevention.
Cohorts to be used are: Scandinavian twin cohorts (Denmark) for growth and development studies, Leiden cohorts for longevity and disease of old age, and the African samples (Leiden) for the studies of life history under adverse conditions.