Molecular basis of aging and longevity

Molecular Basis of
Aging and Longevity
G U A L B E R T O A L A N TAYA J R . / M S T B i o l o g y /
W e s t e r n M i n d a n a o S t a t e U n i v e r s i t y - G r a d u a t e S c h o o l

OUTLINE OF TOPICS:
I. Introduction to Aging: The Biology of Senescence
II. Genes and Aging
a.Genes encoding DNA repair proteins
b.Aging and Signaling cascade
c.Integrating the conserved aging pathways
III. Environmental and Epigenetic Causes
a.Wear-and-tear and genetic instability
b.Oxidative Damage
c.Diet Calorie restriction
d.Young blood: Serum factors and progenitor Cells
IV. Promoting Longevity

Entropy- lack of order or predictability; gradual decline into disorder,
deterioration.
Senescence- the condition or process of deterioration with age and loss of
a cell's power of division and growth.
Exogenous agents- caused by factors (such as food or a traumatic factor)
or an agent (such as a disease-producing organism) from outside the
organism or system.
Endogenous- produced or synthesized within the organism or system.
Progeria- a rare syndrome in children characterized by physical signs and
symptoms suggestive of premature old age.
DEFINITION OF TERMS

Epigenetic- relating to or arising from non genetic influences on gene
expression.
Methylation- the covalent addition of the methyl group at the 5-carbon of the
cytosine ring resulting in 5-methylcytosine (5-mC), also informally known as
the “fifth base” of DNA.
Parabiosis- the anatomical joining of two individuals, especially artificially in
physiological research.
Apoptosis- the death of cells that occurs as a normal and controlled part of
an organism's growth or development.
Loss-of-function mutations- A mutation that results in reduced or abolished
protein function.
Gain-of-function mutations- A mutation that confers new or enhanced
activity on a protein.

INTRODUCTION
Aging is characterized by a progressive loss of
physiological integrity, leading to impaired function and
increased vulnerability to Death. This deterioration is the
primary risk factor for major human pathologies, including
cancer, diabetes, cardiovascular disorders, and
neurodegenerative diseases.
Aging research has experienced an unprecedented
advance over recent years, particularly with the discovery
that the rate of aging is controlled, at least to some extent,
by genetic pathways and biochemical processes
conserved in evolution. (The Hallmarks of Aging, C. Otin et.al., 2013.)

The aging process has two major facets.
1. How long an organism lives;
2. Physiological deterioration, or senescence, that
characterizes old age.
Aging and senescence have both genetic and
environmental components. The interplay between
mutations, environmental, and random epigenetic
change makes these phenomena both fascinating and
frustrating to study.

GENES AND AGING
The maximum lifespan, which is the maximum
number of years any member of a given species
has been known to survive, is characteristic of a
species. The maximum human life span is
estimated to be 121 years.
122 years 150 years Immortal
(transdifferentiation)
150 years 969 years
J.Calment Trout tortoise Methuselah Hydrozoan cnidarian

Genes and Aging
The species-specific life span appears to be determined
by genes that effect a trade-off between early growth and
reproduction and somatic maintenance. In other words, aging
results from natural selection operating more on early survival
and reproduction than on having a vigorous post-reproductive
life. If longevity is a selectable trait, one should expect to find
hereditable variation within populations.
Molecular evidence indicates that certain genetic
components of longevity are conserved between species:
flies, worms, mammals, and even yeast all appear to use the
same set of genes to promote survival and longevity.

GENES ENCODING DNA REPAIR PROTEINS
There are two sets of genes that are well known to be
involved in aging and its prevention, and both sets appear
to be conserved between phyla and even kingdoms of
organisms. These are the 1. genes encoding DNA repair
enzymes and the 2. genes encoding proteins involved
in the insulin signaling pathway.
Individuals of species whose cells have more efficient
DNA repair enzymes live longer. Certain premature aging
syndromes (progerias) in humans appear to be caused by
mutations in such DNA repair enzymes.

Genes encoding proteins involved in the
insulin signaling pathway:
The protein p53 also appears to be important in aging.
This transcription factor, one of the most important
regulators of cell division, has been called the "guardian
of the genome" because of its ability to block cancer in
several ways.
It can stop the cell cycle, cause cellular senescence in
rapidly dividing cells, instruct the Bax genes to initiate
cellular apoptosis, and activate DNA repair enzymes. In
most cells, p53 is bound to another protein that keeps
p53 inactive.

However, ultraviolet radiation, oxidative stress, and other
factors that cause DNA damage will also separate and
activate p53. The induction of apoptosis by p53 can be
beneficial (when destroying cancer cells) or deleterious
(when destroying, say, neurons). It is possible that animals
with high levels of p53 have increased protection against
cancer, but they may also age more rapidly.
Indeed, p53 can be activated by the absence of lamin A
thereby suggesting a mechanism for Hutchinson-Gifford
progeria.

Hutchinson-Gilford progeria
is the result of a dominant
mutation in the gene that
encodes lamin A, a nuclear
membrane protein, and these
same mutations can be seen
in age-related senescence.

Another set of genes important in aging are the sirtuin genes,
which encode histone deacetylation (chromatin silencing)
enzymes. The sirtuin proteins guard the genome, preventing
genes from being expressed at the wrong times and places,
and blocking chromosomal rearrangements.
They are usually found in regions of chromatin (especially
repetitive DNA sequences) where such mistaken chromosomal
rearrangements can occur. However, when DNA strands break (as
inevitably happens as the body ages), sirtuin proteins are called on
to fix them and cannot attend to their usual functions .
Thus genes that are usually silenced become active as the cells
age. Sirtuin proteins have been found to prevent aging throughout
the eukaryotic kingdoms, including in yeasts and mammals.

Genomic instability and telomere attrition. Endogenous or exogenous agents can stimulate a variety of DNA lesions(damage) that are
schematically represented on one single chromosome. Such lesions can be repaired by a variety of mechanisms. Excessive DNA
damage or insufﬁcient DNA repair favors the aging process. Note that both nuclear DNA and mitochondrial DNA (not represented
here) are subjected to age-associated genomic alterations. BER, base excision repair; HR, homologous recombination; NER,
nucleotide excision repair; NHEJ, nonhomologous end-joining; MMR, mismatch repair; ROS, reactive oxygen species; TLS,
translesion synthesis; SAC, spindle assembly checkpoint (Vijg, 2007).

The suppression of signaling by
insulin and insulin-like growth
factor 1 (IGF-1) is one of the ways
life span can be extended in many
species…

DAF-2
(insulin receptor)
AGE-1
DAF-16
(forehead transcription factor)
IGF-1R
( insulin-like growth factor receptor)
PKB
Foxo
InR
( insulin receptor)
Chico
dFoxo
• Protection against ROS
• Activation of DNA repair enzymes
Increased cellular life span
Increased longevity of the
organism
A possible pathway for regulating
longevity. In each case, the insulin
signaling pathway inhibits the synthesis
of proteins that would otherwise protect
cells against oxidative damage caused
by reactive oxygen species (ROS) that
crosslink proteins and can damage DNA.
These protective proteins may be particularly
important in mitochondria. When insulin
signaling is down regulated, forkhead
transcription factors may activate DNA repair
enzymes that may protect against mutations
caused randomly by ROS or other agents. Such
protection against ROS and mutation may
increase the functional life span of the cells and
the longevity of the organism.
The suppression of signaling by insulin and insulin-like growth factor 1 (IGF-1) is one of the ways life span can be extended in many species…

DAF-2
(insulin receptor)
AGE-1
DAF-16
Increased longevity of the organism
Recent studies Caenorhabditis elegans suggest that
there is a conserved genetic pathway that regulates
aging , and that it can be selected for during evolution.
This pathway involves the response to insulin or insulin-
like growth factors.
In C. elegans, a larva proceeds through four larval
stages, after which it becomes an adult. I f the
nematodes are overcrowded or if there is insufficient
food , however, the larva can enter a metabolically
dormant dauer larva stage, a nonfeeding state of
diapause during which development and aging are
suspended.
The nematode can remain in the dauer larva stage for up
to 6 months, rather than becoming an adult that lives
only a few weeks. In this diapausal state, the nematode
has increased resistance to oxygen radicals that can
crosslink proteins and destroy DNA.

DAF-2
(insulin receptor)
AGE-1
DAF-16
Increased longevity of the organism
Favorable environments signal the activation
of the insulin receptor homologue DAF-2 , and
this receptor stimulates the onset of
adulthood. Poor environments fail to activate
the DAF-2 receptor, and dauer formation
ensues . While severe loss-of-function alleles
in this pathway cause the formation of dauer
larvae in any environment, weak mutations in
the insulin signaling pathway enable the
animals to reach adulthood and live four times
longer than wild-type animals.
The pathway that regulates both dauer larva
formation and longevity has been identified as
the insulin signaling pathway.

The increase in DNA synthetic enzymes and in
enzymes that protect against ROS is due to the
DAF-16 transcription factor. This forkhead-type
transcription factor is inhibited by the insulin receptor
(DAF 2) signal. When that signal is absent, DAF-16
can function, and this factor appears to activate the
genes encoding several enzymes (such as catalase
and superoxide dismutase) that are involved in
reducing ROS , several enzymes that increase
protein and lipid turnover, and several stress
proteins.

IGF-1R
( insulin-like growth factor receptor)
PKB
Foxo
organism
Mice with loss-of-function mutations of
the insulin signaling pathway live
longer than their wild-type littermates.
Holzenberger and colleagues (2003)
found that mice heterozygous for the
insulin-like growth factor 1 receptor
(IGF-1R ) not only lived about 30%
longer than their wild-type littermates,
they also had greater resistance to
oxidative stress. In addition, mice
lacking one copy of their IGF-1R gene
lived about 25% longer than wild-type
mice (and had higher ROS resistance,
but otherwise normal physiology and
fertility).

InR
( insulin receptor)
Chico
dFoxo
organism
Flies with weak loss-of-function mutations of the
insulin receptor gene or genes in the insulin
signaling pathway (such as chico) live nearly
85% longer than wild-type. These long-lived
mutants are sterile, and their metabolism
resembles that of flies that are in diapause . The
insulin receptor in Drosophila is thought to
regulate a Forkhead transcription factor (dFoxo)
similar to the DAF-16 protein of C. elegans.
While some evidence points to a correlation
between longer life span, lower insulin
signaling, and elevated ROS protection in
Drosophila, other studies suggest that some
flies and other insects can obtain longer life
spans without increasing the enzymes known to
protect against oxidative stress.

Downregulation of the insulin signaling pathway also
has several other functions:
1. It appears to influence metabolism, decreasing mitochondrial
electron transport. When the DAF-2 receptor is not active ,
organisms have decreased sensitivity to reactive oxygen
species (ROS), metabolic by-products that can damage cell
membranes and proteins and even destroy DNA.
2. Second, downregulating the insulin pathway increases the
production of enzymes that prevent oxidative damage, as well
as DNA repair.
3. Third, this lack of insulin signaling decreases fertility.

ENVIRONMENTAL & EPIGENETIC CAUSES
OF AGING
Most people cannot expect to live 121 years.
Life expectancy—the length of time an
average individual of a given species can
expect to live—is not characteristic of
species, but of populations. It is usually
defined as the age at which half the
population still survives.

Given that in most times and places people did not live
much past the age of 40, our awareness of human aging
is relatively new. A 70-year-old person was exceptional in
1900 but is commonplace today. People in 1900 did not
have the "luxury" of dying from heart attacks or cancers,
because these conditions are most likely to affect people
over 50. Rather, people died (as they are still dying in
many parts of the world) from microbial and viral
infections. Thus, the phenomena of senescence and
the diseases of aging are much more common today
than they were a century ago.

Until recently, relatively few people exhibited the general human
senescent phenotype: gray hair, sagging and wrinkling skin, stiff
joints, osteoporosis (loss of bone calcium), loss of muscle fibers
and muscular strength, memory loss, eyesight deterioration, and
slowed sexual responsiveness.

The general senescent phenotype is
characteristic of each species . But what causes
it? This question can be asked at many levels.
While there is not yet a consensus on what
causes aging (even at the cellular level) theory
is emerging that includes :
1. oxidative stress ,
2. hormones, and
3. DNA damage.*

WEAR-AND-TEAR AND GENETIC INSTABILITY
"Wear-and-tear " theories of aging are among the oldest
hypotheses proposed to account for the human senescent
phenotype. As one gets older, small traumas to the body and
its genome build up .
At the molecular level, the number of point mutations increases,
and the efficiency of the enzymes encoded by our genes
decreases. If mutations occur in a part of the protein synthetic
apparatus, the cell produces a large percentage of faulty proteins.
If mutations were to arise in the DNA-synthesizing enzymes, the
overall rate of mutation in the organism would be expected to
increase markedly.

A new variant of this idea is the hypothesis of
random epigenetic drift. Given that appropriate
methylation is essential for normal development,
one can immediately see that diseases would
result as a consequence of inappropriate
epigenetic methylation. Recent studies have
confirmed that inappropriate methylation can be
the critical factor in aging and cancers. Some of
the evidence for this hypothesis comes from
identical twins.

Most "identical" twins start life with very few
differences in appearance or behaviors, but
accumulate these differences with age.
Fraga and colleagues (2005) found that twin
pairs were nearly indistinguishable in methylation
patterns when young, but older monozygous
twins exhibited very different patterns of
methylation. This affected their gene expression
patterns, such that older twin pairs had different
patterns of DNA expression, while younger twin
pairs had very similar expression patterns.

OXIDATIVE DAMAGE
One major theory views metabolism as the cause
of aging. According to this theory, aging is a result
of metabolism and its by-products, reactive oxygen
species (ROS). The ROS produced by normal
metabolism can oxidize and damage cell
membranes, proteins, and nucleic acids. Some 2-
3% of the oxygen atoms taken up by our
mitochondria are reduced insufficiently and form
ROS : superoxide ions, hydroxyl ("free")
radicals , and hydrogen peroxide.

DIET CALORIE RESTRICTION
One of the few known ways of extending mammalian longevity (again , at
the expense of fertility), and it may do so through several routes:
1. First, restricting calorie intake may reduce levels of IGF-1 and of
circulating insulin.
2. Dietary restriction may also work through the sirtuin proteins thereby
uniting the insulin metabolic pathway with the genomic protection
hypotheses. The insulin pathway in mammals also negatively
regulates Foxo4, the gene for a transcription factor that activates
ROS-protective enzymes.
3. And finally , calorie restriction represses a ribosomal activator whose
absence is associated with increased longevity. So, although calorie
restriction does seem to be able to retard aging, the mechanisms by
which it does so are still controversial.

YOUNG BLOOD : SERUM FACTOR S AND PROGENITOR CELLS

YOUNG BLOOD : SERUM FACTORS AND PROGENITOR
CELLS
One of the hallmarks of aging is the declining ability of stem cells and
progenitor cells to restore damaged or nonfunctioning tissues . A
decline in muscle progenitor (satellite) cell activity when Notch
signaling is lost results in a significant decrease in the ability to
maintain muscle function. Similarly, an age-dependent decline in liver
progenitor cell division impairs liver regeneration due to a decline in
transcription factor cEBP-a.
The problem, however , may not be in the stem cells themselves as
much as in their environment. If an aged and a young mouse are
parabiosed (i.e., their circulatory systems are surgically joined so that
the two mice share one blood supply), the stem cells of the old mouse
are exposed to factors in young blood serum (and vice versa).

PROMOTING LONGEVITY
Several interacting agents may promote longevity. These
include
1. calorie restriction,
2. protection against oxidative stress, and
3. the factors activated by a suppressed insulin
pathway.

It is not yet known how these factors interact— whether
they are part of a single "longevity pathway," or if they act
separately. Mutations are randomly occurring events, and
they may play a role in the aging process.
As advances in our ability to prevent and cure disease
lead to increased human life expectancy, we are still left
with a general aging syndrome that is characteristic
of our species. Unless attention is paid to this general
aging syndrome, we risk ending up like Tithonios, the
miserable wretch of Greek mythology to whom the gods
awarded eternal life , but not eternal youth .

TRIVIA…
Let’s watch this
video!

Most hydrozoans have a
complex life cycle in
which a colonial (polyp)
stage asexually buds off
the sexually mature ,
solitary, adult medusa
(usually called a jellyfish).
Eggs and sperm from the
medusa develop into an
embryo and then a
planula larva . Planula
larvae then form a
colonial polyp stage.

Finally, there may be organisms that have actually cheated death. The
hydrozoan cnidarian Turritopsis nutricula may be such an immortal animal. .
Medusae, like the polyps, have a limited life span, and in most hydrozoans
they die shortly after releasing their gametes (Martin 1997) . Turritopsis,
however , has evolved a remarkable variation on this theme. The solitary
medusa of this species can revert to its polyp stage after becoming sexually
mature.
How does the jellyfish accomplish this feat? Apparently, it can alter the
differentiated state of a cell, transforming it into another cell type. Such a
phenomenon is called transdifferentiation, and is usually seen only when
parts of an organ regenerate . However, it appears to occur normally in the
Turritopsis life cycle. In the transdiffer entiation process , the medusa is
transformed into the stolons and polyps of a hydroid colony . These polyps
feed on zooplankton and soon are budding off new medusae . Thus, it is
possible that organismic death does not occur in this species.

REFERENCES:
S.F. Gilbert, Developmental Biology,9th
Edition.c.2010. P.571-581
C.L. Otin, Hallmarks of Aging. 2013
Strange but Immortal Jellyfish downloaded from
Youtube.
All Images were downloaded from google images

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