In agreement with the last report of the UN on `Aging of the
World-wide Population”, published in 2009, the humanity has
improved its environmental conditions from the century last,
managing to increase the duration of the life in the developed
countries, of 15 years for the men and 22 years for the woman.
Nevertheless, the human beings we are limited to live an average
on 100 years, although exceptional cases of 150 years have been
registered. But some investigators think that we are not
programmed to die, which has impelled to the new science of
the biogerontología to give with the possible keys of the
The human being owns a genetic clock that seems to determine
the time of life, but the process does not happen in the same
way in all the individuals. These genetic variants associated with
the aging, would explain because some people seem to age more
express than others, according to the Nature magazine of
February of 2010.
The science of aging is among the most dynamic and
provocative in modern biology. Over the past two
decades we have seen a virtual explosion in research
investigating the molecular and behavioral systems
that control the aging process. But the more
researchers uncover about the science of aging, the
more questions emerge.
Aging is the progressive loss of physiological functions that
increases the probability of death…..
* The decline in function certainly occurs within cells. This is especially
true of cells that are no longer in the cell cycle
* Neurons in the brain
* Skeletal and cardiac muscle
* Kidney cells
Random mortality from
* Infectious disease
* A harsh environment (e.g.. cold)
* Kills off most animals long before they begin to show signs of aging.
* Even for humans, aging has only become common in recent decades
Loss of structure and function in aging.
Figures represent percentage of a given function remaining in an average 75year-old man compared with that found in an average 30-year-old man, the
latter value taken as 100%.
Weight of brain
Blood supply to brain
Output of heart at rest
Number of glomeruli in kidney
Glomerular filtration rate
Speed of return to normal pH of blood after
Number of taste buds
Strength of hand grip
Maximum O2 uptake during exercise
Number of axons in spinal nerve
Velocity of nerve impulse
LEADIND CAUSES OF DEATH IN MEN AND WOMEN
Chronic obstructive lung disease
Pneumonia and influenze
Programmed in our genes
* Single genes that increase life span in Drosophila,C.elegans, and
* Genes that suppress signaling by insulin and insulin-like growth
factor-1 (Igf-1) increase life span in these animals.
* Mice with one of their Igf-1 receptor genes “Knocked out" live
25% longer than normal mice.
* Antagonistic pleiotrophy. Genes that promote survival early in
life at the expense of maintaining the body will be selected.
* Some examples:
By forcing cells with damaged DNA to stop dividing and
become senescent or even to die by apoptosis, it protects the
organism from the threat of those cells becoming cancerous but
at the expense of reducing cell renewal
The increased life span of yeast
Calorie restriction requires a gene called SIR2 ("Silent
Information Regulator 2")encodes the Sir2 Deacetylase, an
Removes acetyl groups from proteins.
Increasing the activity of Sir2 extends the life span
of yeast, C.elegans, and Drosophila.
But it turns out that mammals have 7 genes that encode
proteins — called sirtuins — similar to Sir2.
*Calorie restriction in mice causes
* A drop in
* The level
of circulating insulin and insulin-like growth
level of glucose and triglycerides in the blood
level of NADH (produced by cellular respiration)
This leads to:
* The production of sirtuins to increase markedly
* Apoptosis of cells to be inhibited
* Formation of Adipose tissue to be suppressed
* Increased production of nitric oxide(NO) which is essential
for the benefits of CR to take effect
* Greatly increased physical activity and lower body weight
* A major aspect of metabolism is the oxidation of foodstuffs by
* Electron transport in the mitochondria generates reactive
oxygen species ("ROS") such as
* The superoxide anion (O2-), which generates
* Hydrogen peroxide (H2O2)
* Although cells contain enzymes catalase which breaks down
H2O2 they eventually and inevitably damage macromolecules in
Link to the
Helps to inhibit
genes that fuel
Boosts genes that
Affect 123 genes
in- volved in
that bump up
signals in cells signaling in tumors
Increase activity of
the p53 gene to
Kill mutant cells
Help to ward off
heart disease, colon
*Cells unless they retain the enzyme telomerase
Lose DNA from the tips of their chromosomes
with each cell division.
The telomeres in the cells of old animals-SHORTER
than in young cells.
*Cells genetically manipulated to express telomerase long
after they should have stopped- avoid replicative
*If telomeres get too short (< 13 repeats in human cells),
chromosome abnormalities — a hallmark of CANCER —
NO Cancer if the cell ceases to divide. So telomere
shortening may protect against cancer at the price of cell
Mice whose genes for telomerase have been "knocked out"
1: The number of Mitochondria in their cells decreases as does the
function of those that remain.
Oxygen consumption and ATP production declines.
The efficiency of the electron transport chain decreases.
This leads to an increased generation of reactive oxygen species(ROS)
2: The level of P53 activity increases.
Apoptosis of cells increases
Replicative senescence increases
3: The anatomy and function of organs such as the liver and heart
show the degenerative changes of age.
Mice given ionizing radiation that damages DNA show early
Transgenic mice with a defect in the "proofreading" function of
the DNA polymerase responsible for copying mitochondrial DNA
accumulate many mutations in their mitochondrial genes;
show marked signs of premature aging.
Cells taken from old mice (and old humans) show slightly
elevated levels of somatic mutations and chromosome
abnormalities like translocations and aneuploidy.
Many of these changes also cause cancer so it is no
accident that the incidence of cancer rises with advancing
The hematopoietic stem cells of knockout mice deficient in
any one of these enzymes needed for genome maintenance
XPD for nucleotide excision repair (NER)
Ku80 for nonhomologous end joining (NHEJ)
TR (telomerase RNA) needed for telomere
maintenance lose their ability to supply the
various progenitor cells that produce the white blood
*Telomere shortening activates p53 which leads to
*The inefficient electron transport chain in damaged
mitochondria produces ROS.
*Abundant nutrients (e.g. amino acids) as well as
other growth stimulants activate TOR which
promotes anabolism (protein and lipid synthesis) with
attendant production of reactive oxygen species
(ROS) and aging.
*Calorie restriction, working through SIRT1 inhibits
TOR and its downstream effects.
*Inhibition of TOR relieves its inhibition
of autophagy allowing the cells to scavenge, for
example, damaged mitochondria.
* Gene expression declined in old age for many genes. Some
* Genes encoding proteins involved in synaptic activity in the
brain (e.g., learning, memory)
* NMDA, AMPA, GABA receptors
* calcium- calmodulin-dependent kinase II (CaMKII)
* Genes involved in mitochondrial functions, such as
* Production of ATP (needed for DNA repair)
* Production of damaging reactive oxygen species (ROS)
Clues from Premature Aging Syndromes
* Werner's syndrome-The hair of patients turns gray in their 20s
and most die in their late 40s with such signs of age
as osteoporosis, cataracts, and atherosclerosis.
* Cockayne syndrome (CS)-. While these people show only some
of the signs of aging, they do have a sharply-reduced life span.
Ataxia telangiectasia (AT)-These patients show signs of
premature aging. They lack a functioning gene (ATM)
product needed to detect DNA damage and initiate a repair
Hutchinson-Gilford progeria syndrome-. Caused by
mutations in the gene (LMNA) for lamin the intermediate
filament protein that stabilizes the inner membrane of
the nuclear envelope.
SOME MODEL ORGANISNS USED IN LONGEVITY
* Single mutants in Caenorhabditis elegans can reduce mortality
threefold and combinations of variants lead to as much as a sixfold
extension in lifespan, increasing to almost eightfold when combined with
* The first longevity mutant to be identified was the C. elegans gene age-
1 that encodes phosphatidylinositol 3-kinase (PI3K) , which has a key role in
a signalling pathway that is homologous to the mammalian insulin–IGF1
(insulin-like growth factor 1) pathway
*The nematode affect mitochondrial function, the so-called
Mit mutants. Starting with the identification of clk-1, and
now involving about a hundred distinct loci, numerous Mit
mutations result in life extension, typically of 20–40% and
sometimes more. Many of these mutants interact with the
insulin–IGF1 pathway mutants to cause life extension
beyond that observed in single-gene mutants alone.
*Two key examples are sir-2 and Tor (Target of
rapamycin), which were identified in yeast and
Drosophila melanogaster, respectively. sir-2 encodes an
NAD-dependent protein deacetylase, which might mediate
the lifespan-extending effects of dietary restriction,
whereas Tor encodes a protein that is involved in sensing
* Many candidate genes have been investigated for putative
associations with human survival or longevity.
* APOE, which is the only gene with common variants that have
consistently been associated with longevity, has an important
role in regulating lipoproteins
* As three isoforms, APOE2, APOE3 and APOE4
* APOE4 has repeatedly been associated with a moderately
increased risk of both cardiovascular disease and Alzheimer
disease, whereas APOE2 is protective
lipoprotein metabolism, microsomal triglyceride
transfer protein (MTTP), has also been implicated
in human longevity.
in the gene encoding angiotensin Iconverting enzyme (ACE) are also biologically
plausible candidates for longevity
*Insulin–IGF1 signalling pathway. The presence
of at least one copy of a specific IGF1R allele
was shown to result in low levels of freeplasma IGF and to be more highly represented
among long-lived individuals. The same study
also reported that different combinations
ofIGF1R and PI3KCB alleles affect free-plasma
IGF1 levels and longevity.
* Immune system genes
* The multifunctional cytokine interleukin 6 (IL6) is
central to this inflammation, and is overexpressed
in many of the stress-related conditions that are
characteristic features of ageing
Outlook: the future of human longevity genetics
* Although there are many biologically plausible
candidates for genes that influence human lifespan,
only one finding has so far been replicated
* Large-scale and carefully designed studies will be
essential for progress in genetic studies of human
longevity. Large international collaborations have
recently been established in the European Union
(the Genetics of Healthy Ageing project
GenomEUtwin) and the United States (the Long Life
Family Study) to identify genetic and non-genetic
factors of importance for exceptional longevity
These studies assess long-lived siblings and controls,
and some of these also include intermediate
phenotypes such as cardiovascular risk factors in
These studies are most promising when combined
with the use of high-throughput genotyping
techniques that make multi-locus analysis (of
haplotypes and gene–gene interactions) and genomewide association studies feasible. Genome-wide
association studies have the advantage that they do
not depend on biologically plausible candidate genes
or knowledge of specific variants.
Large-scale studies are logistically and financially
Understanding the genetic basis for longevity is an
extraordinarily difficult task, but it has the potential
to provide insights into central mechanisms of ageing
The record holder of maximum longevity belongs to France's Jeanne
Calment,who lived to be 122 years and 164 days old. Longevity ran in her
family. Calment's mother lived until she was 86 and her father until he was
94. Her personal outlook of life may also contribute; it is said that she was
immune to stress. She was once quoted: "If you can't do anything about
it,don’t worry about it”
*"Genes are not destiny!" ~ Bruce Lipton, Ph.D.
*The development of an understanding of the true factors
of longevity took place so that they may apply them in
*The false belief constantly being expounded by media
sources as well as through word of mouth conversations,
is disappointing. Longevity genetics are in all of us just
waiting to be activated.
*It cannot be said that way as "I have longevity genes
because my mom lived past the age of 90, so I can eat
and do whatever I want." Here we have the entire field of
biology which is moving along and making
groundbreaking discoveries, yet because of the media's
misunderstandings and seemingly western culture's need
to avoid taking responsibility, people are not seeing the
truth that our health is guided by environmental factors.
However, we are beginning to see changes. The scientists and academics
are beginning to come out with this "new biology" in books and articles
geared towards the public.
Also with the advent of quantum physics, its applications to biology on a
microcosmic level are just becoming unveiled!
The need to bypass the media with information has become necessary since
they've developed ulterior motives and are generally focused on
communicating news from a place of fear and dis-empowerment. (For
example, the media constantly tries to report on the latest possible cancer
"cure" that's just around the corner feeds the public's craving for that onestop-magic-bullet-pill which is never going to exist and stops them from
truly taking control of their lifestyle.) The internet is making this very
possible. It is no coincidence that time and time again, true progress brings
us to a place of empowerment where we can liberate ourselves.
“The true secrets of longevity genetics is in your belief system!”
M. Tech (Biotechnology),
University School of Biotechnology (USBT),
Guru Gobind Singh Indraprastha University,
New Delhi (INDIA)