AGEING

&

Its relationship with

LONGEVITY GENES…

http://www.flickr.com/photos/ynse/542370154/

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 rejuvenation.

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.

*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\

*Starvation

*Predation

*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

Aging is the progressive loss of physiological functions that increases the probability of death…..

Random mortality from

Loss of structure and function in aging. Figures represent percentage of a given function remaining in an average 75-year-old man compared with that found in an average

30-year-old man, the latter value taken as 100%.

Weight of brain 56%Blood supply to brain 80

Output of heart at rest 70

Number of glomeruli in kidney 56

Glomerular filtration rate 69

Speed of return to normal pH of blood after displacement

17

Number of taste buds 36Vital capacity 56

Strength of hand grip 55

Maximum O2 uptake during exercise 40

Number of axons in spinal nerve 63

Velocity of nerve impulse 90Body weight 88

Men Women

01 Heart disease Heart disease02 Cancer Cancer03 Accidents Stroke

04 StrokeChronic

obstructive lung disease

05Chronic obstructive lung

diseaseDiabetes

06 DiabetesAlzheimer's

disease07 Pneumonia and influenze Accidents

08 SuicidePneumonia and

influenze09 Kidney disease Kidney disease10 Live disease Blood infections

LEADIND CAUSES OF DEATH IN MEN AND WOMEN

Programmed in our genes

*Single genes that increase life span in Drosophila,C.elegans, and mice.

*Genes that suppress signaling by insulin and insulin-like growth factor-1 (Igf-1) increase life span in these animals.

*Examples:

*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 DIFFERENT THEORIES OF AGING

The increased life span of yeast

Calorie restriction requires a gene called SIR2 ("Silent Information Regulator 2")encodes the Sir2 Deacetylase, an

enzyme

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.

THE EFFECTS OF CALORIES RESTRICTION(CR)

*Calorie restriction in mice causes*A drop in

*The level of circulating insulin and insulin-like growth factor-1 (Igf-1)

*The level of glucose and triglycerides in the blood

*The level of NADH (produced by cellular respiration) within cells

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

THE FREE RADICAL THEORY OF AGING

*A major aspect of metabolism is the oxidation of foodstuffs by the mitochondria

*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 the cell

*Proteins

*Lipids

FoodLink to the

GenesSpecific

GeneFunction of the Gene

Long-term Effect

Green TeaHelps to inhibit genes that fuel breast cancer

HER-2Triggers growth signals in cells

Slow HER-2 signaling in

tumors

Broccoli

Boosts genes that protect

against heart disease

GST

Produces the body's master antioxidant - glutathione

The additional glutathione helps

keep arteries healthy

Soybeans

Affect 123 genes in- volved in

prostate cancer

p53 Kill mutant cells

Increase activity of the p53 gene to block tumor

formation

Turmeric (a curry

ingredient)

Suppresses genes that bump up

inflammation

Cox-2Makes

inflammatory compounds

Help to ward off heart disease,

colon cancer and Alzheimer's

The Accumulation of Senescent Cells

Chronic

senescence

REPLICATIVEsenescence

TELOMEARSE LENTH

*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 senescence.

*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 senescence.

P53

P16INK4a

TWO PROTEINS ENCODED BY TUMOR SUPPRESSOR

GENES

Play p

ivota

l roles i

n stopping th

e cell c

ycle

The resu

lt: re

plicativ

e senesc

ence

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.

* mitosis declines

*  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.

In the 6 January 2011 issue of Nature, Mariela Jaskelioff and her colleagues (many of the same team that found the results described in the previous section) report that reactivation of telomerase in aged mice reverses many signs of aging

THE ROLE OF TELOMERASE DEFICIENCY IN MAMMALIAN AGING

*Effect of radiation on aging 

Mice given ionizing radiation that damages DNA show early aging.

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 age (graph).

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 cells

The scheme on the right attempts to show how various factors involved in aging

interact. Key players are

Interactions:

*Telomere shortening activates p53 which leads to damaged mitochondria.

*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 examples:

*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 the Transcriptome of Aging Brains

*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.

Clues from Premature Aging Syndromes

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 response.

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.

*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 dietary restriction.

*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

SOME MODEL ORGANISNS USED IN LONGEVITY RESEARCH

*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 amino-acid availability

*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

What has been found so far?

Cardiovascular genes

*In lipoprotein metabolism, microsomal triglyceride transfer protein (MTTP), has also been implicated in human longevity.

*Variants in the gene encoding angiotensin I-converting 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 free-plasma 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.

Metabolism-related genes

*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

*Linkage analysis

*Case–control studies

*Longitudinal studies

Challenges to genetic studies of human lifespan

*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

Outlook: the future of human longevity genetics

These studies assess long-lived siblings and controls, and some of these also include intermediate phenotypes such as cardiovascular risk factors in their offspring.

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 genome-wide 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 demanding

Understanding the genetic basis for longevity is an extraordinarily difficult task, but it has the potential to provide insights into central mechanisms of ageing and disease, which are ultimately hoped to provide targets for the prevention and treatment of late-life disabilities and diseases.

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 their lives.

*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.

CONCLUSION

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 one-stop-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!”

SO….WISH YOU ALL A

“HEALTHY AGING”

By:Nazish Nehal,M. Tech (Biotechnology),University School of Biotechnology (USBT),Guru Gobind Singh Indraprastha University,New Delhi (INDIA)