362
The genetics of aging
Thomas Perls*, Louis Kunkel† and Annibale Puca‡
Once thought to be an extremely complex conundrum of weak
genetic and environmental effects, exceptional longevity is
beginning to yield genetic findings. Numerous lower organism
and mammalian models demonstrate genetic mutations that
increase life-span markedly. These variations, some of them
evolutionarily conserved, inform us about biochemical
pathways that significantly impact upon longevity. Centenarian
studies have also proven useful as they are a cohort that,
relative to younger age groups, lacks genotypes linked to
age-related lethal diseases and premature mortality. Pedigree
studies have demonstrated a significant familial component to
the ability to survive to extreme old age and a recent study
demonstrates a locus on chromosome 4 linked to exceptional
longevity indicating the likely existence of at least one longevity
enabling gene in humans. Thus, a number of laboratories are
making substantial and exciting strides in the understanding of
the genetics of aging and longevity which should lead to the
discovery of genes and ultimately drugs that slow down the
aging process and facilitate people’s ability to delay and
perhaps escape age-associated diseases.
Addresses
*Geriatrics Section, Boston University Medical Center,
88 East Newton Street, F4, Boston, Massachusetts 02118, USA;
e-mail: thomas.perls@bmc.org
† Genetics Division, Howard Hughes Medical Institute,
Children’s Hospital and Harvard Medical School, Boston,
Massachusetts 02115, USA
‡ Centagenetix, 12 Emily Street, Cambridge, Massachusetts 02139, USA
Current Opinion in Genetics & Development 2002, 12:362–369
0959-437X/02/$ — see front matter
© 2002 Elsevier Science Ltd. All rights reserved.
Abbreviations
NAD nicotinamide adenine dinucleotide
RSP relative survival probabilities
WS Werner’s syndrome
Introduction
Average life expectancy has nearly doubled over the past
100 years. In Hong Kong, average life expectancy is
80.1 years and other industrialized nations are running
close behind. In the majority of European countries and
North America, people aged 60 and above comprise 20% of
the population; by 2100 this percentage is expected to rise
to 45% and in Japan it will be 50%. By 2050, 250 million
people (the current size of the American population) in
China will be over the age of 60 [1••]. The population age
85 and older (now 10% of the elderly population) is the
fastest growing segment of our population and over the
next 70 years, this age group will increase four times faster
than the age 65 and older group.
Potentially accompanying this growth of the older segment
of our population will be dramatic increases in the
prevalence of age-related diseases including cardiovascular
and cerebrovascular diseases, diabetes, cancer and
Alzheimer’s disease. The word ‘potentially’ is a key word
here depending upon whether or not baby-boomers choose
to adopt healthier habits. Cures of the major age-related
diseases could result in an average life expectancy of
85 years with a substantial compression of morbidity
towards the ends of people’s lives. Additional improve-
ments in average life expectancy beyond the octogenarian
years will most likely require interventions at the level of
basic mechanisms of aging [2••]. The ability to achieve
exceptional old age in good health is probably a combina-
tion of appropriate health-related behavior, luck, lacking
disease-predisposing genetic variations and possessing
longevity-enabling genes. Even just a few years ago, in
part because of their significant heterogeneity, aging
and age-related diseases were felt to be far too complex
to expect the feasible delineation of genes with specific
and potent effects upon these processes. Now, however,
the genetic study of exceptionally old humans and
other models of exceptional aging such as caloric
restriction and life-span experiments in lower organisms
such as yeast and round worms are yielding exciting and
elucidating findings.
Exceptional longevity within families
Several discoveries relating to the familiality of longevity
and the highly selective nature of centenarians suggest the
viability of studying the exceptionally old and their
families to discover the genetic variations conducive to the
ability to reach these ages. Centenarians represent a cohort
of select survivors who have, at least, markedly delayed
diseases that often cause mortality in the general popula-
tion at significantly younger ages [3]. Because people drop
out of the population due to cardiovascular disease, cancer
and stroke, for example, the distribution of certain
genotypes and other survival-related attributes in a cohort
changes with increasing age; this process is termed
‘demographic selection’. This effect is exemplified by the
drop out of the apolipoprotein E ε-4 allele among the
extreme old [4]. One of its counterparts, the ε-2 allele,
increases in frequency with advanced age among
Caucasians. Presumably the drop out of the ε-4 allele is a
result of its association with ‘premature’ mortality
secondary to Alzheimer’s disease and heart disease.
Along these lines, Silverman et al. [5] hypothesized that
cognitively intact nonagenarians would have an increased
genetic resistance to Alzheimer’s disease relative to
younger individuals. Studying about a thousand probands
without Alzheimer’s disease, grouped into three age
groups, they noted that the cumulative survival without
Alzheimer’s disease was greatest among the first-degree
relatives of the oldest probands, ages 90–102 years [5].

Figure 1
Relative death rates, by sex: siblings of
centenarians versus US 1900 cohort. The
dashed lines at 1.0 and 0.5 represent equal
mortality and half the mortality rate of the
1.0
1900 birth cohort at large.
Mortality ratio
0.8
0.6
0.4
0 5–9
Such findings suggest that centenarians would be ideal
subjects for the discovery of other polymorphisms (or lack
of polymorphisms) associated with a survival advantage.
To further explore the genetic aspects of exceptional old
age, we recently studied 444 centenarian pedigrees
containing 2092 siblings [6••]. Sibling death rates and
survival probabilities were compared to US national levels
using the Social Security Administration’s life table for the
cohort born in 1900. The death rates of the siblings of
centenarians relative to the 1900 birth cohort are illustrated
in Figure 1, revealing a life-long sustained reduction of
mortality risk by approximately one half even up through
very old age.
Normally, mortality rates of different groups (e.g. gender,
race, education, physical activity and socioeconomic status)
converge at very old age, and thus such a sustained
advantage is unusual. The rarity of sustained mortality
differences at older ages in other cases suggests that the
mortality advantage enjoyed by siblings of centenarians
has some significantly influential etiology, perhaps genetic.
Whereas death rates reflect the current intensity of death
at a moment in time, a survival probability reflects the
cumulative experience of death up to that moment in a
cohort’s life history. Thus, a relatively constant advantage
from moment to moment (as seen in the relative death
rates) is translated into an increasing survival advantage
over a lifetime (relative survival probabilities). This
increase is easily seen in Table 1, which indicates the
relative survival probabilities (RSP) for the male and
female siblings of centenarians at various ages.
Note that by age 100, the RSP for women is 8.2 and for
men it is 17. From the analysis of death rates, we know that
the siblings’ mortality advantage does not grow as they get
The genetics of aging Perls, Kunkel and Puca 363
Males
Females
15–19 25–29 35–39 45–49 55–59 65–69 75–79 85–89 95–99
Age
Current Opinion in Genetics & Development
older. Rather, their relative probability of survival is a
cumulative measure and reflects their life-long advantage
over the general population born around the same time.
Such elevated RSP values are important to consider when
weighing the potential utility of performing a sibling-pair
linkage study [7]. Effects of some environmental and
behavioral factors that siblings could have in common early
in life may remain strong throughout life. Some of these
effects might not become evident until older age. In
general, however, environmental characteristics of siblings
such as socio-economic status, lifestyles and region of resi-
dence are likely to diverge as they grow older. Thus if the
survival advantage of the siblings of centenarians is mainly
a result of environmental factors, the advantage should decline
with age. Therefore, the stability of the mortality advantage
over the wide age range would suggest that the advantage
is attributable more to genetic than environmental factors.
The marked increase in RSP and sustained mortality
advantage at extreme ages could be consistent with the
forces of demographic selection in which genes and/or
environmental factors that predispose to longevity win out
over those that are associated with premature or average
mortality. The substantially higher RSP values for men at
older ages supports the hypothesis that, relative to women,
men require a greater ‘dosage’ of these advantages to
achieve extreme ages [8].
Studying Mormon pedigrees from the Utah Population
Database, Kerber and colleagues investigated the impact
of family history upon the longevity of 78,994 individuals
who achieved a minimum age of 65 years [9•]. The relative
risk of survival (λs) calculated for siblings of probands
achieving the 97th percentile of ‘excess longevity’ (for
males, this corresponded with an age of 95 years, and for
women an age of 97 years) was 2.30. A component of the
364 Genetics of disease

Table 1

Relative survival probabilities with 95% confidence intervals (CI) of siblings of centenarians versus US 1900 cohort.

Males Females
Relative survival Relative survival
Age probability Lower 95% CI Upper 95% CI probability Lower 95% CI Upper 95% CI

20 1.00 1.00 1.00 1.00 1.00 1.00

25 1.00 0.99 1.01 1.01 1.00 1.02
30 1.01 1.00 1.02 1.02 1.01 1.03
35 1.01 1.00 1.03 1.03 1.01 1.04
40 1.03 1.01 1.05 1.04 1.02 1.06
45 1.04 1.02 1.06 1.06 1.04 1.07
50 1.08 1.05 1.10 1.08 1.06 1.09
55 1.10 1.07 1.13 1.10 1.08 1.12
60 1.18 1.15 1.21 1.12 1.09 1.14
65 1.29 1.25 1.33 1.16 1.13 1.19
70 1.48 1.42 1.53 1.24 1.21 1.28
75 1.68 1.60 1.77 1.36 1.31 1.41
80 2.03 1.90 2.16 1.54 1.47 1.60
85 2.69 2.47 2.91 1.83 1.73 1.93
90 4.08 3.62 4.54 2.56 2.39 2.74
95 8.35 6.98 9.71 4.15 3.73 4.57
100 16.95 10.84 23.07 8.22 6.55 9.90

lower λs noted in this study compared to our findings
might be due to the younger age of the probands compared
to the probands in our sample who were all at least
100 years old. The Mormon study findings closely agree
with a recent study of the Icelandic population in which
first degree relatives of those living to the 95th percentile
of surviving age were almost twice as likely to also live to
the 95th percentile compared with controls [10]. Both
research groups asserted that the range of recurrent
relative risks that they observed indicated a substantial
genetic component to exceptional longevity that supports
the conduct of molecular genetic studies to locate longevity
enabling genetic loci among sibling pairs.
The average number of very old siblings in the sibships
that we have studied is about three. We have discovered a
few families, however, that have many more siblings
achieving exceptional longevity [11]. The pedigrees
demonstrating vertical transmission of extreme longevity
are shown in Figure 2. Omitted family members died at
age 18 years or younger, or died at an age <90 years because
of trauma. The illustrated gender of certain members was
altered for the sake of anonymity.
Cohort life tables for the years 1900, 1850 and 1801 were
used to estimate the probability of individuals in Figure 2
surviving to their specified ages. For each of these families,
the chances of observing such clustering just by chance are
fewer than one per all the families that exist in the world
today. Thus, the siblings must have something in common
that facilitates such clustering. Several points argue in
favor of shared genetic factors. Two of the four families
include cousins achieving extreme old age and these
relatives are unlikely to have a common childhood
environment. Notably, the spouses of the extremely old
individuals — who were probably exposed to a similar
environment for a substantial portion of the effecteds’ lives
— generally died at average life expectancy. Furthermore,
the four described families come from distinct back-
grounds. Certainly, siblings have many important factors in
common that could contribute to such clustering, including
potent predictors of survival such as education, access to
health care and public health measures. The question
remains though as to what environmental factors that the
siblings might have in common could lead to the sustained
marked mortality reduction for 20 years beyond age 80.
It is worth noting that the above evidence for a substantial
and significant genetic effect on the likelihood of reaching
exceptionally old age is not inconsistent with twin and
Amish studies indicating that the heritability of life-span
considered as a quantitative trait is between 20 and 30%
[12–14]. The results of these studies in which few subjects
survived beyond age 85 should not be interpreted as an
indication of the genetic contribution to achieving much
older age, that is, the nonagenarian years and beyond.
Centenarian families may have certain genetic characteristics
that are highly advantageous but also rare in the population
at large. If so, these differences might have little impact on
the total variation in human life-span, even if their effect is
quite significant for the relatively few individuals
involved. On the other hand, these longevity-associated
alleles could be more common than previously thought
because their existence could be masked by factors that
 The genetics of aging Perls, Kunkel and Puca 365

Figure 2

(a) Family A

? ? 2

? ?
(b) Family B (c) Family C

? ? ? ? ?
?

? ? ? ?
D T D
4
2 + + 4

D ? D D D

(d) Family D

D D D D T D D
5 2
D D ? ? D DD ? ? D D ? D D D

? D ? ?
+ 3 2 2 4 2 2 2 4

D D? ? T D D

Age 90+ years D Cause of death unknown

Age verified T Accident-related cause of death
+ Age 80-89 years in good health ? Birth and/or death date unknown
n Number of individuals Discrepant data, age maybe < 90
Current Opinion in Genetics & Development

Four families demonstrating vertical transmission of extreme longevity.
Omitted family members died at age 18 years or younger, or died at an
age <90 years because of accidental trauma. The illustrated gender of
certain members was altered for anonymity. Ages were validated using
vital records and US Federal census entries. (a) Family A comprises
one male and four females aged 100 or older in one generation living
in the 17th and 18th centuries. (b) In family B, the individuals of note
were born in the 19th or early 20th century and seven are centenarians.
(c) In family C, there is a sibship of 13 children with eight reaching
extreme old age (ranging 90–102 years old). (d) In Family D, there are
two branches linked together by a marriage in the third generation.
These different branches originated from the same small region in
Norway. In the third generation, 23 of 46 individuals achieved extreme
old age (ranging from 90–106 years old).

cause premature mortality such as infectious diseases (that
caused a 25% infant mortality rate until the turn of the
twentieth century), obesity and tobacco use.
Classes of longevity genes
Many studies of lower organisms and mice make the
case for genetic variations that slow the rate of aging and
determine susceptibility to diseases associated with aging.
Summarized in Box 1, Richard Miller at the University of
Michigan, recently proposed a classification of longevity
genes ranging from those hypothesized to either cause or
accelerate aging to those that counteract it [15]. The classes
of longevity genes are discussed below as a means to
describe approaches to discovering genes that influence
aging and longevity. The SAGE KE (Science of Aging
Knowledge Environment) website hosted by Science
Magazine and the Ellison Foundation (http://sageke.
sciencemag.org/cgi/genesdb) maintains a list of candidate
genes and helpful references.
1. Genes that cause aging
It is a point of significant contention as to whether or not
genetic mutations exist in nature that actually either cause
or accelerate aging. Some investigators have proposed a
366 Genetics of disease
Box 1
Hypothetical classification of longevity genes or
their alternatives*.
1. Genes that cause aging (P53?).
2a. Genes that increase the risk of a specific illness early in life but
do not appear to be related to aging (e.g. cystic fibrosis and CF
gene).
2b. Genes that alter longevity because they increase the risk of a
specific illness early in life whose features resemble, to some
extent, some of the consequences of aging (e.g. Werners gene).
3. Genes that influence or cause age-related illnesses (e.g.
Alzheimer’s disease and Apolipoprotein E
-4).
genetically set biological clock that dictates when a species
begins to age. Telomere length and/or telomerase function
have been elected as such a time keeper given their potential
role in regulating the number of cell divisions a mother
cell can subsequently undergo [16]. The number of cell
divisions, in turn, appears to be species-specific and
related to cellular senescence. However, it is unclear what
the selective pressure would be for genetic variations that
would proactively cause aging and ultimately death [17].
Alternatively, declines in telomerase activity with older age
might actually be a defensive measure against the
increased potential for cancer that occurs with age.
Another genetic defense against cancer is the P53 gene.
Donehower and colleagues have noted an increase in P53
activity as a result of a deletion of a portion of one copy of
the P53 gene that is associated with cancer prevention
but also accelerated aging [18••]. None of the 35 mice with
the mutation developed tumors compared to the 45% of
mice without the mutation that did develop cancer. By
96 weeks of age, half the cancer-resistant mutants had died
22 weeks earlier than the normal comparison group and
they developed thinned hair, osteoporosis and impaired
wound healing at a significantly younger age. Consistent
with this are studies in yeast and Caenorhabditis elegans
that sir-2 enhances longevity by turning off P53 and the
observation that cancer incidence generally increases
with age in humans [19]. Among centenarians, however,
we do not observe a trade-off between increased cancer
prevalence and slower aging because life-threatening
cancers are rare in this group. Along these lines, however,
Donehower has noted two out of 217 mice with an
inactive copy of P53 that survived without cancer but also
went on to live much longer than the wild-type [20].
Perhaps these two and future exceptions will yield much
more information.
2a. Genes that increase the risk of a specific illness
early in life but do not appear to be related to aging
The discovery of these genes (e.g. CF gene and cystic
fibrosis) has often been on the basis of linkage studies of
affected family members within single families demon-
strating clustering for the disease or sibling pair studies of
affected members of multiple sibships. There are multiple
examples of these gene discoveries in the literature.
4. Low-fitness genes that extend maximum life-span, probably by
slowing down aging (as observed in lower organism mutations, e.g.
daf genes).
5. Polymorphic genetic loci that influence the rate of aging (many
quantitative trait loci with varying influences on aging and age-
associated diseases).
6. Genes that influence differences in life-span among species (e.g.
longevity enabling genes).
*Adapted from: Miller, RA. A Position Paper on Longevity Genes.
Document URL:
http://sageke.sciencemag.org/cgi/content/full/sageke;2001/9/vp6
2b. Genes that alter longevity because they increase the
risk of a specific illness that resembles some of the
consequences of aging
The progeroid syndromes represent an approach to
discovering genes in humans that play key roles in aging.
Perhaps the most famous of these is Werner’s syndrome
(WS), a rare autosomal recessive disorder characterized by
premature aging. At the molecular level, WS patients
demonstrate significant genomic instability with prevalent
chromosome breaks, translocations and large deletions.
The WS gene, mutation of which underpins this instability,
is a DNA helicase that catalyzes DNA unwinding [21,22].
WS patients presumably age more quickly because they
accumulate DNA damage faster than normal. The helicase
is just one of several aging-related findings of note;
telomerase might play an important role as well. In culture,
fibroblasts from WS patients senesce and stop dividing
after far fewer divisions than normal. Transfecting these
cells with the gene for telomerase extends their life-span
in culture indefinitely [23].
3. Genes that influence or cause age-related illnesses
As with the genes that cause early-life diseases, there are
now numerous examples of genetic variations that substan-
tially predispose to age-related disease (e.g. Alzheimer’s
disease and Apolipoprotein E ε-4). Because these variations
are also associated with increased mortality risk, it is likely
that centenarians do not have many of these predisposing
variations. For example, the Apolipoprotein E ε-4 allele is
rare in this age group [4]. Thus the centenarian genome
may be a useful tool against which to compare the genomes
of individuals with specific age-related and eventually
lethal diseases. Because the frequency of disease alleles is
reduced in centenarians versus ‘generic’ controls selected
from the population, the statistical power of an association
study between centenarians and subjects with a specific
disease should be increased. This should be particularly
true when searching for alleles that have a relatively high
frequency in the general population.
Some important caveats should be raised. For alleles that
are quite rare in the general population, the advantage of
centenarians is quite small. Also, association studies for
complex traits that are not associated with longevity
(e.g. perfect pitch) would not benefit from using centenarians

as controls. Finally, comparing an affected group with a
centenarian sample potentially confounds two different
traits: that of the complex disease being explored and the
longevity trait. As a consequence, such studies will
likely identify both disease-related and other longevity
related alleles.
4. Genetic variations that extend maximum life-span by
possibly slowing down aging
Experiments in yeast [24,25], the nematode C. elegans, in
Drosophila species of flies, and in mice suggest that a few
alleles can exert a powerful influence on life-span. Specific
mutations in C. elegans (daf-2, daf-16, daf-23, age-1 and clk-1)
increase the nematode’s life-span three- to five-fold [26–31].
The daf genes and age-1 regulate the formation of the
hibernating dauer state in C. elegans. The dauer state is an
alternative larval stage that allows the C. elegans worm to
survive periods of low food availability. Well-fed worms live
for about three weeks, but dauer larvae can live more than
two months. The human homologue of daf-2 is the insulin/
IGF-1-receptor [32]. The clk-1 gene controls cell-cycle dura-
tion and adult rhythmic behaviors, and when altered in the
laboratory slows metabolism, also markedly increasing life-
span [33]. Paradoxically, the homologous mutation of daf in
humans would lead to life-shortening insulin resistance, so
it is unclear, at least for the daf class of genes, what their
significance in humans is in terms of longevity.
Studying yeast, Guarente and co-workers [34] have found
that sir-2 (silent information regulator-2), a nicotinamide ade-
nine dinucleotide (NAD) dependent histone deacetylase,
silences large regions of DNA and slows down aging. Aging
in yeast is measured by the number of cell divisions a
mother cell is subsequently able to undergo and the cyto-
plasmic accumulation of circles of ribosomal DNA that are
separate from the main chromosomes. When yeast mother
cells receive an additional copy of sir-2, or when over-
expresion of sir-2.1 (a C. elegans homologue of sir-2) is
induced in C. elegans, both organisms live substantially
longer [35•]. Furthermore, it appears that sir-2 might act as
a sensor to facilitate a cell’s response to changes in meta-
bolic resources. Caloric restriction — which slows down
aging in multiple organisms including yeast, worms, mice
and humans — results in more NAD which, in turn, acti-
vates sir-2 [36••]. Connecting these various observations,
Guarente and Tissenbaum [35•] have found that that
sir-2.1 inhibits genes that influence daf-16 expression,
already noted above to increase life-span when activated.
In Drosophila the methuselah mutant strain survives 35%
longer than wild-types [37]. Over-expression of Cu/Zn
super oxide dismutase can increase the maximum life-span
of transgenic Drosophila up to 48% [38]. Super oxide dis-
mutase plays a critical role in lower organisms and humans
in the scavenging of oxygen radicals [39,40]. Likewise,
longevity-associated daf mutations are associated with an
increased resistance to reactive oxygen species. One
reason for this association is the recent finding that the
The genetics of aging Perls, Kunkel and Puca 367
misexpression of another gene, ctl-1, is necessary for the
increased life-span of the daf-2 and clk-1 mutants.
Cytosolic catalase, which is coded for by ctl-1, may have
evolved to protect the organism from oxidative damage
experienced during the dauer stage prior to reproductive
maturity [41].
In another important finding relating to oxidative damage,
Migliaccio and colleagues recently identified a mutation in
the mouse SHC gene (p66shc) that is associated with a 30%
longer life-span [42]. The protein product of this gene
responds to reactive oxygen species. Ablation of the gene
reduces the apoptotic response to oxidative damage
induced by hydrogen peroxide or ultraviolet irradiation.
Mice with the mutation are also less susceptible to the
effects of paraquat, which causes rapid and lethal oxidative
damage in wild-type animals. These and other findings in
mammals and lower organisms support an important role
for oxidative damage in aging and its modulation by
specific genes [43,44].
One approach to determining the significance of such
genes in humans is to screen for polymorphisms of their
human homologues and determine the allelic frequencies
among specific human phenotypytes such as centenarians
and comparing them to ethnically matched younger
controls or controls predisposed to premature mortality (for
example, children of parents who died prior to average life
expectancy). Picking candidate genes that have already
demonstrated a significant longevity-enabling effect in
lower organisms clearly has its advantages over the much
less specific a priori approach. On the other hand, one must
be prepared for the likelihood that the gene–gene and
gene–environment interactions of a human homologue are
bound to be far more complex than the candidate genes of
lower organisms [45]. Especially in the case of genes such
as daf where the homologous mutation in humans could
lead to life shortening, the discovery that a particular
pathway (such as insulin signaling) is important in
longevity may be just as important as the discovery of a
specific gene.
5. Polymorphic genetic loci that influence the rate of aging
Allelic frequencies can be determined for polymorphisms
of a-priori-selected candidate genes chosen because of
their hypothesized roles in fundamental mechanisms of
aging [46]. These basic mechanisms would include
modulation of genomic instability, for example by DNA
repair and anti-oxidant defenses [47], gene expression [48],
cell proliferation and senescence [49], maintenance of
differential function, and signal transduction.
6. Genes that influence differences in life-span among
species
Richard Miller makes the cogent argument that genes
falling into this category may be relatively few in number
because so many aging-related processes involving many
different cell types occur synchronously and with timing
368 Genetics of disease
that is species-specific [15]. Such synchrony implies
relatively few basic mechanisms, or genes, of aging that
impact upon many different more complex processes and
interactions. Some of the genetic variations noted above
among fly, worm and mouse studies might eventually be
found to have such global influences [50].
Association studies using centenarian sibships may be one
approach to finding these life-span-defining genes. The
existence of families highly clustered for longevity, in
which there may be, for example, five or more centenarian
siblings and multiple cousins, provides the potential
opportunity to perform linkage studies, linking the
extreme longevity phenotype to a specific gene or genes.
Alternatively, the enrollment of many centenarian sibships
can facilitate linkage studies. We recently performed just
such a study. A genome-wide scan for such predisposing
loci was conducted utilizing 308 individuals belonging to
137 sibships demonstrating exceptional longevity. Using
non-parametric analysis, significant evidence for linkage
was noted for chromosome 4 locus at D4S1564 with an
MLS (maximum log score) of 3.65 (p = 0.044). The analysis
was corroborated by a parametric analysis (p = 0.052).
These linkage results indicate the significant likelihood
that there exists a gene or genes that exert a substantial
positive influence upon the ability to achieve exceptional
old age [51••]. The next step will be to replicate this result
with an independent set of families and to proceed with a
single nucleotide polymorphism analysis of the locus in the
attempt to capture the gene playing a significant role in the
marked survival advantage of these individuals.
Conclusions
Genetic studies in lower organisms including mammals
indicate that specific genes have powerful influences upon
life-span. Thus far, investigation of human homologues of
these polymorphisms has not resulted in significant find-
ings. The careful phenotyping of numerous animal and
human models of aging and the collection of genetic mate-
rial along with the current explosion in molecular genetics
data and techniques are nonetheless likely to soon fill
important gaps in the aging puzzle. Complex gene–gene
and gene–environment interactions will certainly complicate
the ability to understand how genes affect aging. However,
taking advantage of demographic selection, studies of cen-
tenarians have already proven to be helpful in deciphering
some polymorphisms and genetic loci either associated or
not associated with exceptional old age.
We anticipate that human longevity-enabling genes will
influence aging at its most basic levels, thus impacting
upon a broad spectrum of genetic and cellular pathways in
a synchronous manner. The centenarian genome should
also be an efficient filter for disease genes. Comparison of
single-nucleotide polymorphism frequencies of genes
implicated in disease between centenarians and individuals
with the diseases should reveal clinically relevant poly-
morphisms. Another approach that researchers are in the
early stages of understanding is differential gene expression
in models known to slow the aging process such as caloric
restriction [52]. Such applications may prove to be another
potent filter for discovering longevity-enabling genes. The
hope, of course, is that these gene discoveries will lead to
the identification of drug targets: drugs that would allow
people to become more centenarian-like by maximizing
the period of their lives spent in good health.
Acknowledgements
We are indebted to the following: The Alzheimer’s Association’s Temple
Discovery Award, the National Institute on Aging (R01AG18721), The
Institute for the Study of Aging, The Paul Beeson Faculty Scholar in Aging
Research Award, and The Ellison Foundation. We thank Bard Geesaman of
Centagenetix for his insightful comments.
References and recommended reading
Papers of particular interest, published within the annual period of review,
have been highlighted as:
• of special interest
•• of outstanding interest
1. Lutz W, Sanderson W, Scherbov S: The end of world population
•• growth. Nature 2001, 412:543-545.
A recent evaluation of how the world’s population is aging and its effect
upon population composition and growth according to age.
2. Olshansky SJ, Carnes BA, Desesquelles A: Demography. Prospects
•• for human longevity. Science 2001, 291:1491-1492.
Widely referenced article predicting the effect of eradicating various
age-associated diseases upon average life expectancy and life-span and
implications for the underlying basic biologic mechanisms of aging.
3. Hitt R, Young-Xu Y, Perls T: Centenarians: the older you get, the
healthier you’ve been. Lancet 1999, 354:652.
4. Schächter F, Faure-Delanef L, Guenot F, Rouger H, Froguel P,
Lesueur-Ginot L: Cohen: genetic associations with human
longevity at the APOE and ACE loci. Nat Genet 1994, 6:29-32.
5. Silverman JM, Smith CJ, Marin DB: Identifying families with likely
genetic protective factors against Alzheimer disease. Am J Hum
Genet 1999, 64:832-838.
6. Perls T, Wilmoth J, Levenson R, Drinkwater M, Cohen M, Bogan H,
•• Erin Joyce E, Brewster S et al.: Life-long sustained mortality
advantage of siblings of centenarians. Proc Natl Acad Sci USA
2002, in press.
The sustained mortality advantage leads to siblings of centenarians having a
8–17 (female, male) times greater probability of surviving to age 100, thus
supporting the utility of conducting genetic studies for the discovery of
longevity genes.
7. Risch N: Linkage strategies for genetically complex traits. II. The
power of affected relative pairs. Am J Hum Genet 1990,
46:229-241.
8. Perls T, Fretts R: Why women live longer than men. Scientific
American Press; June, 1998:100-107.
9. Kerber RA, O’Brien E, Smith KR, Cawthon RM: Familial excess
• longevity in Utah genealogies. J Gerontol A Biol Sci Med Sci 2001,
56:B130-B139.
An ongoing study of the potent Mormon pedigree database and the
interactions between maternal age and proband age in predicting propensity
to achieve exceptional old age.
10. Gudmundsson H, Gudbjartsson DF, Frigge M, Gulcher JR,
Stefansson K: Inheritance of human longevity in Iceland. Eur J
Hum Genet 2000, 8:743-749.
11. Perls T, Shea-Drinkwater M, Bowen-Flynn J, Ridge SB, Kang S,
Joyce E, Daly M, Brewster SJ, Kunkel L, Puca AA: Exceptional
familial clustering for extreme longevity in humans. J Am Geriatr
Soc 2000, 48:1483-1485.
12. McGue M, Vaupel JW, Holm N, Harvald B: Longevity is moderately
heritable in a sample of Danish twins born 1870-1880. J Gerontol
Biol Sci 1993, 48:B237-B244.
13. Finch CE, Tanzi RE: Genetics of aging. Science 1997, 278:407-411.

14. Mitchell BD, Hsueh WC, King TM, Pollin TI, Sorkin J, Agarwala R,
Schaffer AA, Shuldiner AR: Heritability of life span in the Old Order
Amish. Am J Med Genet 2001, 102:346-352.
15. Miller RA: A Position Paper on Longevity Genes.
http://sageke.sciencemag.org/cgi/content/full/sageke;2001/9/vp6.
16. Blackburn EH: Structure and function of telomeres. Nature 1991,
350:569-573.
17. Harrison DE: Potential misinterpretations using models of
accelerated aging. Gerontol Biol Sci 1994, 49:B245-B246.
18. Tyner SD, Venkatachalam S, Choi J, Jones S, Ghebranious N,
•• Igelmann H, Lu X, Soron G, Cooper B, Brayton C et al.: p53 mutant
mice that display early ageing-associated phenotypes. Nature
2002, 415:45-53.
High-profile paper indicating the possibility of a mutation associated with
accelerated aging and cancer resistance.
19. Luo J, Nikolaev AY, Imai S, Chen D, Su F, Shiloh A, Guarente L, Gu W:
Negative control of p53 by Sir-2 alpha promotes cell survival
under stress. Cell 2001, 107:137-148.
20. Strauss E: Cancer-stalling system accelerates aging. Science
2002, 295:28-29.
21. Yu CE, Oshima J, Fu YH, Wijsman EM, Hisama F, Alisch R,
Matthews S, Nakura J, Miki T, Ouais S et al.: Positional cloning of
the Werner’s syndrome gene. Science 1996, 272:258-262.
22. Gray MD, Shen JC, Kamath-Loeb AS, Blank A, Sopher BL,
Martin GM, Oshima J, Loeb LA: The Werner syndrome protein is a
DNA helicase. Nat Genet 1997, 17:100-103.
23. Wyllie F, Jones C, Skinner J, Haughton MF, Wallis C, Wynford-Thomas D,
Faragher RG, Kipling D: Telomerase prevents the accelerated cell
ageing of Werner syndrome fibroblasts. Nat Genet 2000, 24:16-17.
24. Imai S-I, Armstrong CM, Kaeberlein M, Guarente L: Transcriptional
silencing and longevity protein Sir2 is an NAD-dependent histone
deacetylase. Nature 2000, 403:795-800.
25. Jazwinski SM: Molecular mechanisms of yeast longevity. Trends
Microbiol 1999, 7:247-252.
26. Van Voorhies WA, Ward S: Genetic and environmental conditions
that increase longevity in Caenorhabditis elegans decrease
metabolic rate. Proc Natl Acad Sci USA 1999, 96:11399-11403.
27. Larsen PL: Aging and resistance to oxidative damage in
Caenorhabditis elegans. Proc Natl Acad Sci USA 1993, 90:8905-8909.
28. Lin K, Dorman JB, Rodan A, Kenyon C: daf-16: an HNF-3/forkhead
family member that can function to double the life-span of
Caenorhabditis elegans. Science 1977, 278:1319-1322.
29. Lakowski B, Hekimi S: Determination of life-span in Caenorhabditis
elegans by four clock genes. Science 1996, 272:1010-1013.
30. Hsin H, Kenyon C: Signals from the reproductive system regulate
the lifespan of C. elegans. Nature 1999, 399:362-366.
31. Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R: C. elegans mutant
that lives twice as long as wild type. Nature 1993, 366:461-464.
32. Kimura KD, Tissenbaum HA, Liu Y, Ruvkun G: daf-2, an insulin
receptor-like gene that regulates longevity and diapause in
Caenorhabditis elegans. Science 1997, 277:942-946.
33. Ewbank JJ, Barnes TM, Lakowski B, Lussier M, Bussey H, Hekemi S:
Structural and functional conservation of the Caenorhabditis
elegans timing gene clk-1. Science 1997, 275:980-983.
34. Vaziri H, Dessain SK, Ng Eaton E, Imai SI, Frye RA, Pandita TK,
Guarente L, Weinberg RA: hSIR2(SIRT1) functions as an
NAD-dependent p53 deacetylase. Cell 2001, 107:149-159.
35. Tissenbaum HA, Guarente L: Increased dosage of a sir-2 gene
• extends lifespan in Caenorhabditis elegans. Nature 2001,
410:227-230.
Important finding because unlike yeast, the C. elegans cells are post-
mitotic. Thus the maintenance of chromatin structure and the role of NAD in
life-span may be pertinent to higher organisms.
The genetics of aging Perls, Kunkel and Puca 369
36. Lin SJ, Defossez PA, Guarente L: Requirement of NAD and sir2 for
•• life-span extension by calorie restriction in Saccharomyces
cerevisiae. Science 2000, 289:2126-2128.
This study establishes a mechanism by which the cell translates metabolic
needs (e.g. increased glycolysis) in the face of caloric restriction leading to
increased NAD levels that, in turn, activates sir-2 and this then leads to the
activation of daf-16 and therefore life-span extension. This pathway appears
to have been evolutionarily conserved going from mitotic yeast to post-
mitotic cells in C. elegans.
37. Lin YJ, Seroude L, Benzer S: Extended life-span and stress
resistance in the Drosophila mutant methuselah. Science 1998,
282:943-946.
38. Parkes TL, Elia AJ, Dickinson D, Hilliker AJ, Phillips JP, Boulianne GL:
Extension of Drosophila lifespan by overexpression of human
SOD1 in motorneurons. Nat Genet 1998, 19:171-174.
39. Williams MD, Van Remmen H, Conrad CC, Huang TT, Epstein CJ,
Richardson A: Increased oxidative damage is correlated to
altered mitochondrial function in heterozygous manganese
superoxide dismutase knockout mice. J Biol Chem 1998,
273:28510-28515.
40. Sohal RS, Ku HH, Agarwal S, Foster MJ, Lal H: Oxidative damage,
mitochondrial oxidant generation and antioxidant defenses during
aging and in response to food restriction in the mouse. Mech
Ageing Dev 1994, 74:121-133.
41. Taub J, Lau JF, Ma C, Hoque R, Rothblatt J, Chalfie M: A cytosolic
catalase is needed to extend adult lifespan in C. elegans. Nature
1999, 399:162-166.
42. Migliaccio E, Giorgio M, Mele S, Pelicci G, Reboldi P, Pandolfi PP,
Lanfrancone L, Pelicci PG: The p66shc adaptor protein controls
oxidative stress response and life span in mammals. Nature 1999,
402:309-313.
43. Sun J, Tower J: FLP recombinase-mediated induction of
Cu/Zn-superoxide dismutase transgene expression can
extend the life span of adult Drosophila. Mol Cell Biol 1999,
19:216-228.
44. de Haan G, Gelman R, Watson A, Yunis E, Van Zant G: A putative
gene causes variability in lifespan among genotypically identical
mice. Nat Genet 1998, 19:114-116.
45. NIA Aging and Genetic Epidemiology Working Group: Genetic
epidemiologic studies on age-specified traits. Am J Epidemiol
2000, 152:1003-1008.
46. Schächter F: Causes, effects, and constraints in the genetics of
human longevity. Am J Hum Genet 1998, 62:1008-1014.
47. Dollé MET, Giese H, Hopkins CL, Martus HJ, Housdorff JM, Vijg J:
Rapid accumulation of genome rearrangements in liver but not in
brain of old mice. Nat Genet 1997, 17:431-434.
48. Lee CK, Klopp RG, Weindruch R, Prolla TA: Gene expression profile
of aging and its retardation by caloric restriction. Science 1999,
285:1390-1393.
49. Warner HR, Hodes RJ, Pocinki K: What does cell death have to do
with aging? J Am Geriatr Soc 1997, 45:1140-1146.
50. Martin GM, Austad SN, Johnson TE: Genetic analysis of ageing:
role of oxidative damage and environmental stresses. Nat Genet
1996, 13:25-34.
51. Puca AA, Daly MJ, Brewster SJ, Matise TC, Barrett J,
•• Shea-Drinkwater M, Kang S, Joyce E, Nicoli J, Benson E et al.:
A genome-wide scan for linkage to human exceptional longevity
identifies a locus on chromosome 4. Proc Natl Acad Sci USA
2001, 98:10505-10508.
First sib-pair study of centenarians to demonstrate positive linkage. These
findings still require verification by other centenarian studies. In the
meantime, the authors are pursuing the gene responsible for linkage.
52. Lee CK, Klopp RG, Weindruch R, Prolla TA: Gene expression profile
of aging and its retardation by caloric restriction. Science 1999,
285:1390-1393.