ISSN 20790570, Advances in Gerontology, 2014, Vol. 4, No. 4, pp. 238246. Pleiades Publishing, Ltd., 2014.

Original Russian Text V.S. Baranov, O.S. Glotov, E.V. Baranova, 2014, published in Uspekhi Gerontologii, 2014, Vol. 27, No. 2, pp. 247256.

New Genetic and Epigenetic Approaches in Gerontology

V. S. Baranova, O. S. Glotova, and E. V. Baranovab
a

Ott Research Institute of Obstetrics and Gynecology, Northwest Branch, Russian Academy of Sciences,
ul. Mendeleevskaya liniya 3, St. Petersburg, 199034 Russia
email: baranov@vb2475.spb.edu
b
European Institute of Personalized Medicine and Health, ul. Pastorelli 38, MonacoNice, France

AbstractThis paper presents an overview of the most significant discoveries and findings in gerontology for
20112014. It considers results of the whole genome association studies (GWAS), obtained in a representa
tive cohort of centenarians, protective mutations of Alzheimers disease, new data on the role of the hypo
thalamus as a command center of human aging, results of experimental studies of the geroprotective and anti
carcinogenic action of rapamycin and metformin, and metadata indicating a negative effect of antioxidants
in the treatment of lung cancer. Special attention is paid to the problems of aging epigenetics and epigenetic
mechanisms of gene activity regulation. Data on the longterm epigenetic effects that affect stable repro
gramming of the genome at an early age and clinical observations and experimental data demonstrating the
transgenerational transmission of epigenetic changes in the parents to their offspring are examined. There has
been a tendency emerging in recent years to the transfer from studies of the dormant genome (anatomy of the
genome) to the study of the dynamic genome (its physiology), which opens up new opportunities to clarify
the underlying mechanisms of aging and ways of maintaining active longevity.
Keywords: centenarians, protective mutation, command aging center, rapamycin, metformin, antioxidants,
epigenetic mechanisms
DOI: 10.1134/S2079057014040055

INTRODUCTION
Aging and death are essential elements of the
ontogeny of any organism, including humans. The
main task of gerontology is not so much to slow down
the aging process of a person as to maximize the period
of active longevity. The 21st century, witnesses of
which we happen to be, certainly is the century of
Genetics, or rather, after the human genome and
genomes of thousands of other organisms have been
deciphered, the century of Genomics.
According to recent data, the basis of aging bio
mechanisms is genomic instability, telomere shorten
ing, dysfunction of mitochondria, cellular senescence,
epigenetic changes, dysregulation of exchange of
nutrients, protein instability, depletion of stem cells,
changes in intercellular communication, and the reac
tion of inflammation [38]. Each of these biomecha
nisms is based on a wealth of experimental data, is sup
ported by relevant theories, and is the basis for the
development of appropriate geroprotectors. The prob
lems of genomics and epigenomics of aging have been
studied extensively in the scientific literature [1, 8
10]. This topical issue has periodically been covered in
our articles and reviews [26, 12, 48]. However,
genomics is developing so rapidly and its achievements
are so significant that a periodic review is still valuable.
This article presents an overview of the main and
most important, according to the authors, discoveries

and original research in the field of gerontology, and

specifies some promising areas of research of aging
biomechanisms and possible ways of their correction.
1. GENOMIC RESEARCH
It was noted earlier that the aging process is a
depletion of functioning of the cell genome and a slow
degeneration of the transcriptome of cells, which var
iously manifest themselves in cells of different organs
and tissues (the body as a mosaic of organs of different
age) [3, 4]. The key role in aging processes is played by
special genesageregulated genes, as well as genes
candidates of many serious chronic multifactorial dis
eases (MFDs) (weak link genes), which make a sub
stantial contribution to premature aging and mortality.
Lists of already known genes of aging, as well as genes
of common MFDs, are given in many reviews and
monographs [1, 6, 9, 10].
A significant part of these genes has been identified
by genome wide association studies (GWAS). It
should be noted that one of the genes confirmed by
GWAS was a gene from a family of sirtuins (SIRT).
Another candidate gene was gene TERC, encoding
one of the peptide fragments of the telomerase com
plex (see below) [6].
The comparative analysis with the use of GWAS of
1000 individuals aged 90 and 60107 years and 1200 con

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trol subjects identified 28 genes whose analysis allows

predicting the longevity with an accuracy of 60%. The
comparative studies with the use of GWAS also
allowed detecting in the genome of centenarians about
150 singlenucleotide substitutions (SNPs) which dis
tinguished them from middleaged individuals. It is
assumed that their testing allows identifying potential
longlivers with a probability of about 77% [46]. Fur
ther studies showed that the analysis of the results of
the genetic profile of centenarians should be consid
ered very carefully, especially its predictive power. It
was established, in particular, that the contribution of
genetic factors to longevity increases progressively
with age. Genes are responsible for nearly 2030% of
differences in the survival in patients older than
85 years. An unexpected finding was the fact that the
frequency of alleles of candidate genes of frequent
chronic MFDs in centenarians was the same as in the
population. The impression is, with few exceptions,
that most of the previously identified weak link
genes, that is, genes of predisposition to MFDs, do
not play an important role in the maximum lifespan.
There are real longevity gene networks, in owners of
which aging diseases develop much later than usual. At
the same time, as shown by genomewide analysis,
genetic profiles of centenarians can be different and be
divided into several subgroups [46].
2. GENES AND MUTATIONS
ASSOCIATED WITH LONGEVITY
It is known that an important role in longevity
belongs to mutations in key metabolic genes, such as
the gene of the insulinlike growth factor receptor
(IGFR), the gene of microsomal cholesterol transfer
protein (CETP), and some mutations in mitochon
drial genes [1, 6]. Of particular interest are mutations
of the protective effect. Recently, there was discovered
a mutation (A673T) in the amyloid protein gene
APP, preventing the development of Alzheimers dis
ease [35]. As a result of replacement of threonine
amino acid for alanine, the mutant protein loses a
restriction site for the enzyme BACE1, there is no
depletion of protein APP and no amyloid which
forms fibrillar structures that kill neurons. In people
over 85 years without Alzheimers disease symptoms,
the frequency of this mutation is 45 times higher
than in the population. The protective effect of this
mutation confirms the amyloid hypothesis of
Alzheimers disease pathogenesis and opens new ways
for drug therapy of this disease. The main thing now is
to find early markers (predictors) of Alzheimers dis
ease, as symptoms appear only 1015 years after the
beginning of the formation of amyloid fibrils. Specific
miRNAs, as shown by recent studies, can serve as
these predictors [17].
Among the many already known genes of longev
ity, particular attention in recent years was given to
genes of the family of sirtuinsregulatory genes
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whose favorable effect on health and longevity is simi

lar to that of limiting the energy value of nutrition. The
positive effect of genes of this family has previously
been shown in different organisms (yeast, worms, and
flies). It was also found that limiting the energy value
of nutrition activates sirtuin genes. In 2012, this effect
was proven in mice [52], although the exact mecha
nism of its action is not fully understood. Despite some
inconsistency in the existing data [27], the important
role of sirtuin genes for longevity is not in doubt. It
became especially evident after discovering in the
hypothalamus the command aging center (see below).
A protective role against aging is also played by
generegulatory gene P16, whose expression induces
apoptosis of aging cells. The latter are known to
actively produce inflammatory moleculescytokines
that affect the neighboring healthy cells. Relieving the
body from aging and apoptotic cells is regarded as one
of the possible ways to lengthen the lifespan [24].
Another important gene for ensuring a normal
lifespan and aging delay is AUF1, whose product
reduces inflammation and suppresses the immune
response, reduces the number of agedependent dis
eases, including cancer. Its product, protein AUF1, is
critical for binding and degradation of mRNA tran
scripts of inflammatory genes (cytokines). Mice with
knockout of gene AUF1 showed rapidly progressing
signs of aging, resembling those at reduced levels of
telomerase. Further studies showed that protein AUF1
binds to the promoter part of the telomerase gene and
activates its transcription [43].
In this regard, it is worth noting that the enzyme
telomerase, for the discovery of which in 2009 three
researchers (E. Blackburn, Carol Greider, and Jack
Szostak) were awarded with the Nobel Prize, contin
ues to attract the attention of not only scientists, but
also commercial firms [14]. It has been found that
telomere length to a certain extent can be used as an
indicator of human health and its biological age.
Telomere shortening is associated with the risk of car
diovascular disease, frequency of cancer, diabetes,
Alzheimers disease, and disorders of the immune sys
tem; that is, it induces the beginning of many illnesses
that are often classified as diseases of aging and old age
[1]. It has been established that psychological stress
influences and shocks in childhood contribute to
telomere shortening, while sports and a measured way
of life promotes an increase in their length. Determi
nation of telomere length is considered as an impor
tant clinical test. It is believed that telomere length
does not allow predicting the life expectancy, but indi
cates the age of onset of agerelated diseases.
Soon after discovering the telomeres and determin
ing their role as a cellular clock, there appeared special
companies not only for testing the telomere length,
but also for the development of tools to assist its elon
gation. In 2005, the U.S. firm TASciences (Telom
erase Activation Sciences) suggested dietary herbal
supplements for the conservation and elongation of

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Hypothalamus

Fig. 1. Hypothalamusaging command center [Zhang

et al., 2013]. Limitation of the energy value of nutrition is
the most reliable way towards active longevity. The rela
tionship of genes of the hypothalamus and the function of
immune cells regulate aging processes. NFkB activation
in the hypothalamus stimulates the immune response,
production of CD4+ Tcells, strengthens the immune sys
tem and the likelihood of autoimmune diseases, and inhib
its the synthesis of reproduction hormones GmRH. Sir
tuin genes (SIRT1) in the hypothalamus suppress the
activity of NFkB genes, reduce the production of CD4+
Tcells, and weaken the immune system. Activators of the
gene SIRT1 are starvation, physical activity, and red wine
(resveratrol).

telomeres. In the absence of rigorous evidence of the

utility of the test and possible complications associated
with the administration of this BAA, the company was
fined and its activities were suspended [31]. However,
the telomeric genetic test is still very popular. None
theless, the interpretation of the results of such a test is
very difficult and very subjective.
3. THE HYPOTHALAMUS AS THE COMMAND
CENTER OF AGING
One of the most important events in gerontology in
recent years was the discovery of the crucial coordinat
ing and even commanding role in the aging process in
mammals of the subcortical structure of the brain
the hypothalamus [51]. In experiments on mice, it was
shown that inflammation in the hypothalamus dis
rupts cognitive processes and is accompanied by
degenerative processes of many tissues. At least partly
these effects are associated with suppression of the syn
thesis of gonadotropinreleasing hormone (GnRH)
which stimulates neurogenesis, brain cell metabolism,
and reproduction and growth processes. Under the
action of proinflammatory cytokines, transcription
nuclear factor NFkb activates in cells of the hypo
thalamus, including, in turn, genes of the immune
response and inflammation. Activity of factor NFkb,
as shown in experiments, is minimal in cells of the
hypothalamus of young mice, but progressively

increases with aging. Activation of the NFkb factor by

its natural inducer protein IKK led to weight loss,
lesion of bones and cartilages, atrophy of muscles and
skin, and inhibition of functions of all lifesupport sys
tems. Gene products of the NFkb factor and IKK
inhibited GnRH gene expression and broke the cycle of
reproduction, that is, dramatically accelerated all pro
cesses of natural aging. It was known previously that
inflammation in the hypothalamus accelerates aging
of peripheral tissues, but this work has clearly estab
lished that the hypothalamus can act as a master regu
lator of aging. In humans, it means the emergence of
new approaches to slowing aging by direct exposure of
the brain and hypothalamus to antiinflammatory
substances. This way one can expect promising new
targets for antiaging pharmaceuticals (see Fig. 1).
Indeed, as noted previously (see above), anti
inflammatory factor AUF1 has a geroprotective prop
erty and reduces the inflammatory response and the
number of agedependent diseases [43]. However,
inflammation and inhibition of the synthesis of hor
mones is only one part of the gerontological cycle in
the hypothalamus, which includes mechanisms of
aging. There is, as has now been established, another
part of the cycle, aimed at slowing down the aging pro
cess [41]. The principal agent of this cycle is sirtuin
genes, which are expressed by special hypothalamic
neurons (AGRP, agoutirelated peptide expressing
neurons). Sirtuin proteins prevent inflammation and
reduce the activity of CD4+ Tcells. In mice with Sirtuin
SIRT1 gene knockout, the content of CD4+ Tcells is
increased, but the number of Tregulatory cells is
decreased; autoimmune reactions are marked (see
Fig. 1). Thus, through the sirtuin genes, the hypothal
amus can actively influence the immune system. Low
calorie diets stimulate the synthesis of sirtuin in hypo
thalamic cells and also reduce the inflammatory
effect. On the contrary, plenty of food leads to a drop
in the level of SIRT1 and provokes an immune
response. Presently there are studies in humans on
how fasting can suppress the harmful autoimmune
effect and, on the contrary, how food stimulates an
immune response.
Thus, it is in the hypothalamus where basic ways of
accelerating (1) and slowing (2) of aging processes
converge. The first includes proinflammatory cytok
inesactivation of NFkb and IKK genesinflam
matory responseinduction of autoimmune pro
cessesaging of the body. The second may be initiated
by a lowcalorie diet and physical activity, which
induce the expression of sirtuin genesactivation of
gene GnRH, weakening of the immune response, and
body rejuvenation.
4. PHARMACOLOGICAL DRUGS THAT SLOW
DOWN THE AGING PROCESS
At the moment, gerontology is focused on the
search for drugs that act on different units of the met
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241

Hypothalamus

Metformin

GHRH

Hypophysis
Dwarf mice Ames

GH

Insulin

GHreceptor

GHR /
Limitation of the energy value of nutrition

IGF1

InR

IGF1 receptor

Igf1 +/

Fig. 2. Probable paths of the action of metformin, limitation of the energy value of nutrition, and genetic modifications on the
signaling pathway of growth hormoneinsulinIGF1 (according to Anisimov et al., 2003).

abolic pathways and slow down the aging process. The

most encouraging results in this regard were obtained
for the drugs rapamycin and metformin.
Rapamycin
Rapamycin is an antibiotic isolated from bacteria
of medical mud Rapa nuy in 1965. It is widely used for
the treatment of patients after renal transplantation, is
a specific inhibitor of the metabolic pathway mTOR
(Mammalian Target of Rapamycine), and involves the
enzyme serine/threoninekinase which is important
for cell metabolism and aging [23]. Metabolic pathway
mTORkinase is involved in billions of cellular
responses from autophagy to synthesis of cellular pro
teins. Many mutations associated with longevity
reduce the activity of this pathway and switch the body
to the metabolism characteristic for limiting the
energy value of nutrition (path 2, see Section 3). Pre
viously it was shown that rapamycin, mTORkinase
inhibitor, lengthens the life of fruit flies, yeast, and
nematode worms. Recently it was established that
rapamycin has a geroprotective effect in mice [23]. In
a twoyear experiment in mice, it was shown that this
antibiotic inhibits weight gain, slows down all signs of
aging, extends the lifespan, and reduces the incidence
of tumors.
This work had a great response and stimulated
numerous studies [29, 37, 47]. It was found that the
reduction in mTOR activity increases the average
lifespan in mice by an average of 16%, inhibits expres
sion of gene P16 and genes of polyubiquitin proteins,
and reduces the frequency of infectious diseases. In
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general, the phenotypic effects of reduced activity of

mTOR resembled those in limiting the energy value of
nutrition. It was suggested that inhibition of the meta
bolic pathway mTOR affects the aging process itself
rather than blocking some single mechanism or reac
tion in this complex process [50].
Thus, the mechanism of the geroprotective action
of rapamycin agrees well with the aforementioned
hypothalamuscontrolled way of increasing the
lifespan (see Section 3).
Metformin
In 1970, V.M. Dilman expressed the idea that
antidiabetic biguanides may be promising geroprotec
tors and anticancer drugs (V.M. Dilman, 1970). This
fruitful idea, as shown by further studies, proved to be
prophetic. Metformin (phenformin) not only reduced
insulin and glucose levels in the blood, but also increase
the lifespan of mice [18, 21, 22, 30]. In addition, the drug
had antitumor action and blocked the metabolic pathway
AMPK/mTOR/S6K1 and decreased the activity of sev
eral protein kinases, including receptors of tyrosine
kinases HER1 & HER2 which are critical for the growth
of breast cancer cells [2022]. Disorders of the insulin
and TORmetabolic pathways explained the hypoglyce
mic and antitumor effect of metformin, as well as its anti
geriatric properties (see Fig. 2). The increase in life
expectancy under the action of metformin was shown in
yeast, worms, insects, and mice [20, 40].
Metformin and rapamycin, according to V.N. Anisi
mov, can be considered as key drugs for the study of the
relationship of aging processes at the cellular level, for

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the whole organism, and for tumor growth [19]. Both

the drugs delay aging of cells or lead to apoptosis and
autophagy. Death of senescent cells is a protective
mechanism from their possible transformation into
tumor cells. Indeed, special studies showed that the
selective death of senescent cells increases the lifespan
of mice, as well as safeguards them from the develop
ment of cancer. Furthermore, senescent cells start to
secrete proinflammatory cytokines that trigger inflam
matory responses in adjacent, healthy cells. Creating
drugs or artificial activation of genes that kill senescent
cells is considered nowadays as a new possible way of
lengthening life expectancy [24].
Antioxidants
The free radical theory of aging of D. Harman and
N.M. Emanuel, which postulates a crucial role of
reactive oxygen species (ROS), continues to be at the
center of many studies and is the basis for the search
for and development of new pharmaceuticals with
antioxidant activity [1]. A vast amount of experimental
data confirm the mutagenic effect of these compounds
and their carcinogenic properties [1, 25]. Recently
RAS Academician V.P. Skulachev developed a new
promising class of antioxidants for ROS neutralization,
which has been successfully tested in clinical trials.
However, it should be noted that in recent years the
attitude towards antioxidants as promoters of carcino
genesis has changed significantly. In 2011, the first
report was published that ROS compounds, which
were always considered to be inducers of cancer, in
fact, may be useful, since they themselves inhibit
tumor growth [45]. In 2014, Swedish authors pub
lished a thorough investigation in which they found
that wellknown antioxidants such as vitamin E and
Nacetylcysteine promote the growth of lung tumors
in mice [44]. As it turned out, this is due to the fact that
antioxidants neutralize ROS in all cells of the body,
both normal and tumor. Their abundance leads to
lower concentrations of ROS and a decreasing
mutagenic effect, which contributes to tumor growth;
that is, antioxidants have a potentiating carcinogenic
effect. Furthermore, as has been established, antioxi
dants also significantly reduce expression of gene p53
in tumor cells, which promotes their survival and
aggravates the adverse situation. By the way, in 1994, it
was noted that in smokers who took betacarotene, an
antioxidant, lung cancer was observed more frequently
than in smokers who were not taking this antioxidant.
Carried out in 2012, a metaanalysis of 72 trials of
antioxidant therapy in lung cancer patients confirmed
this conclusion. A similar mechanism of action of
antioxidants is observed in human cells. It remains
unclear whether this effect is limited only to lung can
cer or has a general nature and may be observed in
other tumors.

5. AGING EPIGENETICS
The aging process, as well as closely related chronic
diseases (diseases of aging), has a typical multifactorial
nature; that is, aging occurs not only due to genetic but
also epigenetic factors governing the genomes opera
tion. Violations of epigenetic regulation are one of the
main causes of changes in gene expression during
aging. According to the epigenetic theory of aging, not
only genetic mutations are accumulated with age, but
also many nonadaptive epigenetic changes (epimuta
tions) that disrupt transcription of genes and desyn
chronize their work. Epigenetic changes occur
throughout life. They are stable and inherited during
mitosis. There is increasing evidence that they can be
transmitted transgenerationally, that is, be inherited by
several generations (see below).
Epigenetic factors directly or indirectly affect the
functional activity of the genome, leading to stable
changes that do not affect the primary structure of
DNA (nucleotide sequence), but play a crucial role in
the regulation of genes. Known mechanisms of epige
netic variability and regulation of genomes function
ing are very diverse and include methylation of DNA
(of cytosine nucleotides), acetylation or methylation of
histone proteins that stabilize the structure of DNA,
regulatory microRNAs, specific target genes, and spi
ralization (heterochromatization) of DNA strands; all
of these invalidate individual genes or DNA fragments
for transcription enzymes. Different mobile elements
of the genome, transposons, may also act as transcrip
tion regulators. The contribution of these epigenetic
changes to the aging process is just beginning to be
explored. The obtained results are very contradictory
and are limited mainly by analysis of DNA methyla
tion.
Described 40 years ago, agerelated DNA demeth
ylation in mammalian cells in different tissues of one
body is expressed in different ways and may be associ
ated with blast transformation. As experiments have
shown, DNA demethylation in brain cells correlates
with impairment in cognitive abilities and memory. It
is characteristic for brain cells in Alzheimers disease
[42]. An increase in activity of enzyme Dnmt3a2,
which adds a methyl group to cytosine, restores mem
ory in mice. It is assumed that methylation blocks the
function of an unknown generepressor of memory.
Low levels of the enzyme Dnmt3a2 were found in the
brain of old mice, while its repression in young mice
impairs memory. In the cells of the hippocampus,
DNA methylation decreases during training, which
leads to the activation of gene Arcthe main marker
of learning, but increases with aging of rats [26]. Age
related hypermethylation, indicating functional inac
tivation, was observed for many genes and rather long
DNA sequences and is characteristic for both aging
cells and tumor cells.
Promoters of rRNA genes and many of the struc
tural genes in cells of the brain and other tissues glo
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bally hypermethylate with age. At the same time, there is

a global demethylation of repetitive sequences, including
mobile genetic elementstransposons [10].
The association of DNA spiralization (its hetero
chromatization) with longevity has been shown for
yeast, worms, and fruit flies and recently was con
firmed on the model of replicative cellular aging in
mice [49]. In addition to changes in the methylation
pattern of genes and their promoters, it is believed that
histone acetylation (histone code) plays an important
role in the regulation of aging processes. In experi
ments on mice, it was shown that with aging in cells in
the ear DNA methylation increases and histone acety
lation reduces; that is, transcriptome activity progres
sively decreases [49].
Until recently, decreasing heterochromatization of
nuclei in senescent cells was regarded as a characteris
tic feature of cellular aging, but recent evidence sug
gests that with age the nucleus accumulates hetero
chromatic loci and their movement in the chromo
somes, which significantly affects the spectrum and
the functional activity of their adjacent genes.
Epigenetic changes in DNA occur throughout the
life, starting in gametogenesis and in the early stages of
embryogenesis and, of course, continue at postnatal
stages. They are stably inherited during mitosis. To
understand the mechanisms of aging, it is important to
note that epigenetic changes, including the tendency
to longevity may be transmitted with gametes, that is,
be inherited. Transgenerational transmission of epige
netic traits has been demonstrated in plants, fruit flies,
worms, and mice [17, 32]. Moreover, experiments on
worms in 2011 found that epigenetic changes leading
to an increase in life expectancy can be inherited at
least within three generations [33].
Transgenerational transmission of epigenetic
changes was shown in humans too. Children in Den
mark, whose grandfathers had suffered a period of
severe famine in 19381939, showed a significantly
increased incidence of diabetes mellitus type 2 and
cardiovascular diseases [34]. Similar trends are shown
for the residents of besieged Leningrad [15, 36].
It is known that living conditions in early child
hood have a lasting effect on subsequent development,
directly influencing DNA methylation. One study car
ried out in the UK in 2011 compared the DNA meth
ylation profiles of 40 people from different social
groups. There were found 6000 genes, including 1252
promoter regions, with sharp differences in methyla
tion depending on the quality of life in childhood.
However, it remains unclear at what age these epige
netic differences are established and how they affect
the future life [39]. Serious pathology in the cardiovas
cular system and the liver was found in elderly people
who had survived the siege of Leningrad in their child
hood. Apparently, the cause of this somatic pathology
is persistent epigenetic changes in the genomes func
tioning, which had been caused by the famine [15, 36].
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Problems of distant manifestations of epigenetic

changes in the genome, induced by exogenous factors
for various phenotypic traits including aging and
MFDs, are just beginning to be developed. However,
there is increasing evidence that such changes may not
only be manifested later in life, but even be transmitted
to descendants. Transgenerational genetic effects in
humans are shown for diabetes type 2 and some
tumors [13]. Along with the features of our genome,
our way of life, and deeds, we define not only the qual
ity of our life, but also predetermine the health and
lives of our children.
CONCLUSIONS
Recent years have witnessed significant progress in
the study of aging processes. This progress concerns
clarification and correction of existing and justifica
tion of new provisions of gerontology, the shift of
research interests towards epigenetics, and finding
solutions to problems of gerontology in the field of sys
tem genetics.
As the analysis of the literature and our data show
[12, 48], studies aimed at finding candidate genes of
aging have not led to breakthrough discoveries even
with the use of new molecular techniques. However,
some important facts have emerged. It was found that
the genes with susceptibility to multifactorial diseases
do not substantially affect the maximum lifespan;
genomewide analysis can identify sets of polymor
phic sites (SNPs) with a high probability associated
with longevity; individual life expectancy and even
longevity cannot be predicted only by the results of
genetic testing without family and medical history.
Of great interest for aging genetics is the detection
of a protective mutation in the amyloid protein, which
prevents the development of Alzheimers disease. The
presence of this mutation provides new opportunities
to search for drugs against dementia.
The most striking development of recent years was
the identification of the hypothalamus as the com
mand center of aging. In fairness it should be noted
that the idea of the central role of the hypothalamus in
aging belongs to Professor V.M. Dilman and is the
basis of the neuroendocrine theory of aging (1975). In
this theory, the emphasis was on agerelated changes
in the receptor apparatus of hypothalamic cells and
impairment of its hormonal function. According to
the latest concepts, the hypothalamus can both accel
erate and slow the aging process [51]. Acceleration of
aging occurs due to inflammatory responses in hypo
thalamic cells mediated by factor NFkB, and its delay
is stimulated by products of sirtuin genes activated by
reducing the energy value of nutrition. Of course,
many aspects of this hypothesis still need to be clari
fied, but its attractive aspect is that it brings together
many previously known facts and gerontological phe
nomena. It is in light of this hypothesis that the gero
protective action of limiting the energy value of nutri

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tion, the function of sirtuin genes, and the value of

pharmaceuticals such as rapamycin and metformin
become clearer. It also explains the acceleration of
aging caused by proinflammatory cytokines and the
adverse effect of sick and dying cells on aging processes
in the body.
As for the other wellknown theories of aging, the
most recent data, if not in conflict with them, chal
lenge some of their provisions. In particular, the telo
meric hypothesis of aging (theory of marginotomy) of
A.M. Olovnikov [11] became widely known after the
discovery of the telomerase enzyme (2009), and the
telomeric test for estimating the length of telomeric
ends of chromosomes even began to be used to predict
health. However, today the attitude towards this test
remains very skeptical, and drugs for artificial telom
ere elongation were officially banned in 2012 due to
lack of rigorous evidence of the relationship between
the telomere length, health, and the human lifespan.
Even more difficult is the case with the free radical
theory of aging of D. HarmanH.M. Emanuel [1].
Recent observations suggest that peroxygen com
pounds not only damage cells but can be toxic to
tumor cells, thus suppressing ROS by antioxidants in
tumor cells can only exacerbate the development of
lung cancer.
In summing up the extensive data of the last few
years on the genetics of aging and longevity, it becomes
apparent that solely analyzing the genes and their
mutations is unlikely to provide an understanding of
complex processes that involve thousands of genes,
hundreds of metabolic pathways, and billions of
chemical reactions.
It is believed that the share of inheritance in human
health is only about 30%, and that health is mostly
determined by external factorsby about 70%. Con
sequently, it is diverse external factors (diet, lifestyle,
habits, etc.) that make a decisive contribution to
implementation of individual genomes features [5].
As shown by genomewide analysis of candidate genes
of multifactorial diseases and aging genes by GWAS,
the contribution of genetic factors to the development
of many chronic diseases, including diseases of
aging, usually does not exceed 1015% [5]. There
fore, testing of candidate genes, gene panels, and hun
dreds of polymorphic sites associated with longevity
does not allow achieving a level sufficient for the indi
vidual prediction of life expectancy. The modest role
of genes themselves in shaping the complex phenotype
is likely due to the complexity of mechanisms of inter
genic, supramolecular, and intercellular interactions,
features of the regulation of gene activity, difficulties of
objective assessment of the real contribution of exter
nal factors, etc. It is not accidental that recently stud
ies of the molecular nature of multifactorial diseases
pay ever more attention to functions of candidate
genes and epigenetic mechanisms of regulation of
their activity. Valuable information on agerelated
characteristics of the genomes operation is provided

by analyses of transcriptome profiles [1], as well as by

studies of methylation profiles of different tissues.
Testing of the entire genome today is rather of an
intellectualaesthetic value, but is unlikely to be useful
in everyday life. Genetic data without consideration of
the lifestyle and personal traits of the patient always
lead to errors. The results of genetic testing, including
longevity genes, are only the beginning of hard and
responsible work of the expert in creating an individual
genomic/epigenetic program of gene regulation [5].
Only the study of the functional rather than static
genome may be a way out of the dead end of missing
heritability and the inability to properly interpret the
results of genetic testing, which is always a result of
common analysis of allelic variants of candidate genes
[7]. A good illustration of this is the recent publication
concerning the possibility of correction of expression
of unfavorable gene variants using diet [28]. For exam
ple, in a study carried out in Spain, 7000 people were
divided into three equal groups, one of which for five
years received a vegetal lowcalorie Mediterranean
diet (PREDIMED), which, as has been found, signif
icantly modifies expression of transcription factor
TCF7L2 associated with diabetes type 2 and metabolic
syndrome. Longterm use of this diet significantly
reduced blood glucose levels and significantly (up to
the population level) reduced the incidence of stroke
and myocardial infarction in patients with a high
hereditary risk of cardiovascular diseasehomozy
gotes or heterozygotes by the unfavorable allele of
gene TCF7L2.
The sad experience of genetic testing for hereditary
predisposition to multifactorial diseases [4, 5] shows
that the modern approach to the problems of geron
tology should be based on the positions of epigenetic
medicine, that is, individual analysis of the function of
candidate genes and the study of their transcriptional
and metabolic profiles and possibilities of epigenetic
correction of unfavorable alleles [7, 16]. Research and
selection of groups should be carried out with the
obligatory account of anamnestic data, clinical his
tory, and results of laboratory tests. It is on the way of
targeted epigenetic influences aimed at correcting the
attenuated variants of genes; that is, taking into
account individual clinical features of the genome,
one can expect significant progress in maintaining
active longevity and achieve the maximum natural
lifespan.
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Translation by K. Lazarev

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