Genetics of longevity and aging

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Genetics of longevity and aging

• Hiljar Sibul
• 15.05.2007

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Longevity Miracle - Devraha Baba at 250 Years
Old.
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This map shows the worldwide distribution of
people over 65 years old. http//www.worldmapper.o
rg/

• 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.

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Median age
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World Population Ageing  1950-2050

• Population ageing is unprecedented, without
  parallel in human historyand 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.

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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).

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Life expectancy world map2005
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Ageing - A Challenge of Our Time

• 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?

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Living Longer

• 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.

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Genetics of Longevity Key Questions

• 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?

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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) lt0.33
• 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)
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• 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

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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
  bodys 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.

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Biological TheoriesII

• Autoimmune Theory
• This is the idea that aging results from gradual
  decline in the bodys 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.

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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.
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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.
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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 ---------------------- gt OH. OH-
  O2

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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
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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
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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.

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• 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. .

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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.

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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").
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• The records are
• for mice 4
• for dogs 29
• for cats 34
• for goldfish 492
• 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)

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From the model organisms (e.g. S. cerevisiae,
D. melanogaster, C. elegans), clear candidate
genetic pathways and mechanisms underpinning
ageing and longevity have emerged.
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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-gtlife-extension
• Spe-26 - reduced fertility/life-extension
• WRN (Werner syndrome) DNA helicase, RecQ family
  (human)
• Sir2 - NAD)-dependent histone deacetylase
  (deletions shorten life span)

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• 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

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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
• eat genes 100-150 (caloric restriction)
• sperm production mutant - 165 (trading off
  fertility versus longevity)

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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.

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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.

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• 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 gt 30 October 1998 gt Lin et al.,

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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) lt0.33
• 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
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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.

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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.

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• 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 (plt0.001)
• Frequency of the ?2 allele significantly
  increased (plt0.01).
• Schachter et al., 1994
• ApoE2 protects against cardiovascular disease and
  Alzheimers disease.

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• 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.

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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 (gt99 years old,
  159 women and 31 men) and in 260 lt60 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 lt 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

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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)

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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

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(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

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Conclusions

• 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.

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European 6th frame program - LifeSpan WP08
genetic variation and life span
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• 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.

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• 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.

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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.

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• 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.

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Hans Baldung Grien's The Ages And Death, c.
1540-1543