Sunday, August 12, 2012

I Want to Live Forever

     Methuselah is the oldest person whose age is mentioned in the Hebrew Bible. Methuselah was the son of Enoch and the grandfather of Noah and tradition suggests that he died  at the age of 969 years, seven days before the beginning of the Great Flood.

     Today, 'Methuselah', or 'as old as Methuselah' is often used to refer to any living thing reaching great age. The oldest living tree in the world is a White Mountains, California, bristlecone pine (Pinus longaeva) named Methuselah, after the biblical character.
     The Methuselah tree, found at 11,000 feet above sea level, is 4,838 years old and is the oldest living non-clonal organism in the world. But even older than Methuselah (the tree) was Prometheus. In 1964, a graduate student, was taking core samples from a tree named Prometheus. After breaking his boring tool inside the tree,  he asked for permission from the US Forest Service to cut it down and examine the full cross-section of the wood. Prometheus (once cut down) turned out to be about 5,000 years old.
     Silene stenophylla is a species of flowering plant commonly called narrow-leafed campion. A frozen specimen of the fruit was found in a (very old) squirrel's cache and the germinated plants bore viable seeds. The fruit was dated to be over  31,800 years old.
The Methuselah Tree

     Microbial species have been noted to have a type of 'extended longevity'. Credible researchers have claimed 'resuscitation' of bacterial spores to an active metabolic state, the spores having been embedded in amber for 40 million years as well as spores from salt deposits in New Mexico being revived after 240 million years.
     One scientist was able to coax 34,000 year old salt-captured bacteria to reproduce and his results were confirmed and duplicated at a separate independent laboratory facility.
Black Coral Genus Leiopathes

     There are many other long-lived species. Specimens of the black coral genus Leiopathes are among the oldest continuously living organisms on the planet, thought to be over 4,265 years old. The giant barrel sponge Xestospongia muta is known as one of the longest-lived animals, with the largest specimens in the Caribbean estimated to be older than 2,300 years. There are some species of sponges in the ocean near Antarctica which  are thought to be over 10,000 years old.
     Certain animals have a 'biological immortality' such as the hydrozoan species (small, predatory animals related to jellyfish and corals) Turritopsis nutricula which is able to cycle from a mature adult stage to an immature polyp stage and back again with the implication that  there may be no natural limit to its life span.
Barrel Sponge Xestospongia Muta

     Even the larvae of carrion beetles have been shown to be capable of undergoing 'reversed development' when starved growing back at a later stage to the previously attained level of maturity.
     Clonal plant colonies are not considered by all researchers to be a single organism but some of these 'colonies' are connected by (huge) single root system and all have the same genetic make-up.
     Pando is a Quaking Aspen tree or clonal colony that has been estimated at 80,000 years old (possibly as old as one million years, all 'members' of the 'colony' connected to each other via a single massive underground root system.
     The biology of longevity and ageing, investigation of the role of genes has focused on the nematode (worm) Caenorhabditis elegans (C. elegans). The genome of this species has been fully sequenced with 97,000,000 base pair genome and has a normal life span of 2-3 weeks. Several mutations have been identified in C. elegans which alter the rate of ageing, with some mutants living more than five times as long as wild-type worms.
Quaking Aspen Tree Clonal Colony

     Although immortality has not been achieved, life expectancy for human beings has been greatly extended over the past 2000 years. By the 1980's, the world average life expectancy reached 62 years but this figure varies hugely across the globe.
     The average life expectancy of a population has always been greatly affected by death rate at or around the time of birth. Countries or eras of history where health care was poor and infant mortality high, skewed the life 'expectancy' of that population to the low side.
Caenorhabditis Elegans (C. Elegans)

     Life expectancy at birth between 50,000 and 10,000 years ago was about 33 years. Life expectancy then fell until Medieval times (due to conflict?). For instance, in classical Greece and Rome, this number was 28 years.
     In Medieval Britain and Medieval Islamic Caliphate (about the 10-12th centuries), life expectancy rose to 30-35 years.
     In early 'modern' Britain (the 16th, 17th, and 18th centuries), life expectancy ranged from 25-40 years, in early 20th century Britain, 31 years and in 2010, the world average life expectancy at birth rose to 62 years.
Medieval Islamic Caliphate

     Often, life expectancy may increase with age as the individual survives the higher mortality rates associated with childhood. In Medieval Britain, for example, life expectancy at birth was 30 years. But a male member of the English aristocracy at the same period, having survived to the age of 21, could expect to live to between 64 and 71 years old.
     Before the Industrial Revolution, death at young and middle age was common and lifespans over 70 years were rare. This was not due to genetics, but rather due to environmental factors such as disease, accidents, and malnutrition. Death during childbirth was common in women and many children did not live past infancy due to disease or trauma. Even when people did attain old age, they were likely to die quickly from untreatable disease or infection.
The Industrial Revolution

     Differences in life expectancy between different parts of the world are caused mostly by differences in public health services, medical care and diet. Much of the excess mortality (higher death rates) in poorer nations is due to war, starvation, and diseases such as malaria and AIDS.
     The effect of AIDS is especially notable on life expectancy in many African countries. If HIV was not a factor, the life expectancy at birth for 2010–2015  would have been 70.7 years instead of 31.6 in Botswana, 69.9 years instead of 41.5 in South Africa and 70.5 years instead of 31.8 in Zimbabwe.
     Even in countries where there is a majority of  people are of European ethnic background, such as the United States, Britain, or Ireland,  those with an African ethnic background still tend to have shorter life expectancies than their European counterparts. In the United States, for instance, 'Euro-Americans' have a life expectancy of 78.2, but 'African Americans' only 73.6 years.
Mozambique and Malawi

     Apart from 'ethnicity' (a large part of which is genetic make-up), economic and political factors also have significant bearing on life expectancy. The lowest life expectancies are in the African countries of Malawi and Mozambique where the average life span is just 36 years. The highest life expectancies are in Japan, Andorra and San Marino, where life expectancies are between 80 and 83 years.
     It is evident that many factors contribute to an individual's longevity, including gender, genetics, hygiene and access to health care, diet and nutrition, lifestyle and exercise as ell as crime rates. In developed countries, life expectancy varies between 77 and 83 years (ex Canada 81.29 years in 2010); in developing countries, life expectancy is much more variable between 32 and 80 years (ex Mozambique 41.37 years in 2010).
     Many studies suggest that longevity is based on two major factors, genetics and lifestyle choices.  Studies involving twins show that approximately 20-30% of an individual’s lifespan is related to genetics and the rest is due to individual behaviors and environmental factors. After reaching the age of 80 years, lifestyle plays almost no role in health and longevity and almost everything that 'keeps you going' in advanced age is due to genetic factors.
     Scientific and objective study of longevity has only been practised in recent decades. Prior to that, historical accounts of long-lived 'methusalahs' are impossible to verify.
Jeanne Calment

     The longest-lived well documented case is that of a French woman Jeanne Calment who died in August 1997 at the age of 122 years, 164 days. Of the ten documented 'long-livers', all are female and all are from developed countries (France, US, Canada, Japan) with the exception of one from Ecuador.
     But does all this mean that we are 'supposed to die', that we are 'not supposed to live to 122 years'? Why then do members of some species live hundreds, even thousands of years and why do some of our own species outlive the rest of us?
     Aubrey David Nicholas Jasper de Grey  is an English author and theoretician in the field of old age research and the Chief Science Officer of the 'Strategies for Engineered Negligible Senescence (SENS) Foundation'.
     He is best known for his view that human beings could, in theory, live to lifespans far in excess of 122 years, perhaps even to thousands of years. Indeed, Grey claims that the first human who will live up to 1,000 years is probably already alive now, and might even be today between 50 and 60 years old.
Aubrey David Nicholas Jasper de Grey

     De Grey claims to have identified seven types of molecular and cellular damage caused by essential metabolic processes - 'The Seven Deadly Things' (that number '7' once again! see post: Seven Sages and Four Horsemen):
     1. Cancer-causing nuclear mutations: Changes (mutations) to the nuclear DNA (nDNA), the molecule that contains our genetic information, or to proteins which bind to the nDNA can lead to cancer. For the purposes of SENS, the effect of mutation which really matters is cancer which can spread and become deadly. The solution would be a 'cure for cancer'. The SENS program focuses on regenerative medicine treatments to lengthen telomeres (see cellular senescence, below), protecting the ends of the DNA molecule.

     2. Mitochondrial mutations: Mitochondria are tiny 'energy factories' within our cells which contain their own genetic material. Mutations to mitochondrial DNA (mDNA) can affect a cell’s ability to function properly. Because of the highly oxidative environment in mitochondria and the lack of the repair systems normally found in the cell nucleus but absent in mitochondria, mitochondrial mutations are believed to a be a major cause of progressive cellular degeneration and ageing. Moving the mDNA into the cellular nucleus where it would be better protected might solve this problem.
     3. Intracellular aggregates (junk inside the cell): Our cells are constantly breaking down molecules which are no longer useful or which can be harmful and which can’t be digested. These molecules accumulate as junk inside our cells, resulting in diseases such as atherosclerosis and macular degeneration.  Removal of this intracellular junk by adding new enzymes (taken from bacteria and molds) to the human cell would be the solution.

     4. Extracellular aggregates (junk outside of the cell): Harmful junk can also accumulate outside of our cells. The amyloid plaque seen in the brains of Alzheimer's patients is an example. This extracellular might be removed by enhancing the immune system and by using drugs to break chemical bonds within the junk. The larger junk in this class could also be removed surgically.
     5. Cell loss: Some of the cells in our bodies cannot be replaced, or can only be replaced very slowly. This decrease in cell number causes problems such as a weakened heart and Parkinson's Disease. This cell depletion can be partly corrected by exercise and growth factor administration but more complete cell replacement would require stem cell therapy and 'tissue engineering'.
Parkinson's Disease

     6. Cellular senescence: Cell senescence is a phenomenon where the cells are no longer able to divide but also do not die. Often, these cells secrete harmful. Type 2 diabetes and joint degeneration (arthritis) are examples of this phenomenon.  These same cells sometimes do not respond to usual signals within the organism as part of a process called apoptosis (programmed cell death) where the cells are genetically instructed to destroy themselves.
     Cells in this senescent state could be eliminated by forcing them to apoptose by inserting 'suicide genes' or vaccines into these cells, allowing healthy cells to multiply and replace them.
     Cellular senescence relates once again to the telomeres which are pieces of DNA that act as a kind of protective end to the chromosome. When a cell divides the telomere curls back around to continue to protect the end but each time the cell divides, the telomere gets shorter. Eventually the telomere becomes too short to curl back far enough and can no longer properly protect the chromosome.
Leonard Haflick

     Cancer cells are be able to produce an enzyme called telomerase that the cancerous cell uses to rebuild its telomeres and continue dividing beyond its assumed 'allotted' amount.
     The reality is that in all multicellular organisms, no individual cell is meant to live forever. There is, a programmed cell death (apoptosis) genetically ingrained into each cell. This has been defined as the Hayflick limit  (Hayflick Phenomenon), the number of times a normal cell population will divide before it stops, presumably because the telomeres shorten to a critical length.
     The Hayflick limit was discovered by Leonard Haflick in 1961, at the Wistar Institute in Philadelphia. Hayflick showed that each cell division shortens the telomeres on the DNA of the cell, eventually makes cell division impossible, this shortening correlating with the ageing process. Between 50 and 70 billion cells die each day due to apoptosis (the Hayflick limit) in the average human adult.
     7. Extracellular crosslinks: Cells are held together by special linking proteins. When too many cross-links form between cells in a tissue, that tissue can lose its elasticity and cause problems such as arteriosclerosis and presbyopia. De Grey proposes to develop enzymes to break links caused by sugar-bonding, known as advanced glycation end-products and other forms of chemical linking.
The SIR2 Gene

     But despite all these somewhat 'specific' points which, if addressed, may prolong life, science does not really know exactly why we age. What is known is that there are a large number of gene sequences which play a role in the process of aging.
     One of the major contributors to aging may be the SIR2 gene (producing the SIR2 protein) and its effects on metabolism. The SIR2 gene is a 'controller', turning on some genes within a cell and turning off others. Other research has found correlations between a  the use of calories in a cell and life span (in flies), doubling not only the life span of the insect but also their 'middle age'.
     Aubrey de Gray may have recognized some of the factors which result in ageing and pointed in the direction of possible solutions but there is already clinical research which has produced results.
     The University of Texas Southwestern Medical Center is researching the use of telomerase in cells other than cancerous cells in the hope of extending the ability of these healthy cells to continue to divide. The idea is that if we can stay healthier for longer then the likelihood is that we can, in fact, live longer.
     Three types of cloning are being investigated:
Dolly the Sheep

1. Recombinant DNA Technology or DNA Cloning involves cloning a specific gene.
2. Reproductive Cloning  transferred genetic material from the nucleus of an adult donor cell to a enucleated egg. This egg is then stimulated to encourage division and once a suitable stage has been achieved, the egg is transferred to a uterus and brought to term. This technique was used to produce Dolly the sheep.
3.Therapeutic Cloning (embryo cloning) is similar to reproductive cloning but the embryo is not returned to the uterus and is not intended to be brought to term. The embryo is used as a source for embryonic stem cells which can then be used to produce any kind of organ or tissue which will have a DNA match to the cell donor.
     Organ production is already a reality. It has been revealed that a cell taken from an udder, for instance, could produce a liver or heart or, as in the case of Dolly, a whole sheep. If we can genetically engineer or clone a new organ to replace the one that is faulty, we could ultimately live a very much extended life.
Human Ear on the Back of a Mouse

     In 1997, at the University of Massachusetts, researchers were able to grow a human ear on the back of a mouse. The study was designed to serves as a model for tissue engineering. The mouse had a defective immune system and was unable to reject the human tissue.
     Medicine can already, replace some defective organs by transplanting a donated organ but the donor organ must be a tissue match. If the donor tissue and the recipient's tissue don't match then the organ is rejected and therefore useless.
     Human urinary bladders have been created and inserted with success into recipients using their own cloned cells. In 2000, the scientists who created Dolly created cloned pigs, pig organs being the mostly likely ones to be able to be used for xenotransplantation (genetically modifying animal organs, tissue and cells for use in human transplantation).
     Ultimately while it does not strictly lengthen our life span, whole body cloning may provide the ultimate in immortality. If we can extract our DNA and transplant or store it we really do have the opportunity to 'live forever'.

     But there are perhaps more 'practical' ways to extend life expectancy already available - at least in certain non-human species. Resveratrol, a compound found in the skin of red grapes was reported to extend the lifespan of yeast, worms, and flies.
     Calorie restriction in mice has been shown to extend life span by around 40% even when initiated late in the animal's life. The activity of the gene SIR2 has been shown to increase under calorie restriction (see 'Extracellular crosslinks', above).
     Intermittent fasting, such as alternate day fasting, resulting in low-calorie intake can also extend life span.
     Dietary restriction of the amino acid methionine also produce extended longevity in mice.

      A certain breed of mouse with an absence of growth hormone has been shown to live 60-70% longer than the standard laboratory mouse species. This research demonstrates that the hormone insulin and insulin-like growth factor (IGF-1) along with growth hormone are important to the operations of metabolism that determine life span.
     In 2008, Spanish researchers were able to extend life span in lab mice by 50% through a combination of an enhanced telomerase enzyme and p53 gene. Telomerase, produced by cancer cells extends cell life but creates a cancer while the p53 gene is an anti-cancer gene that normally reduces life span, lowering the risk of cancer. The telomerase-p53 experiment effectively demonstrates a point of balance between extended life span and cancer.
The p53 Gene

     Inactivation or reducing the activity of the CLK-1 gene (originally noted in C. elegans) found in mitochondria boosts mouse longevity by 30%.
     A Russian researcher has demonstrated a form of antioxidant that can be targeted to the mitochondria when ingested. SkQ, the mitochondrially targeted antioxidant boosts mouse life span by 30%.
     Genetically manipulating the levels of a naturally produced antioxidant catalase in order to increase its level in the mitochondria increases mouse life span, presumably by soaking up some portion of the free radicals produced by mitochondria before they can cause damage. The mice lived 20 percent longer than the normal variety.
     An enzyme called pregnancy-associated plasma protein A (PAPP-A) which operates within the insulin-like growth factor system, when removed, extends a mouse's life span by 30% without reduced calorie intake and, at the same time, reducing the incidence of cancer.
     Mice lacking the gene for the adenylyl cyclase type 5 (AC5) protein live 30% longer. This heart gene (AC5), when 'knocked out', besides allowing the mice to live longer, also seemed to prevent heart stress as well as bone deterioration that often accompanies ageing.

     The drug metformin (commonly used to treat diabetes) acts similarly to calorie restriction in mice, resulting in 10% gain in maximum life span.
     Fat-specific insulin receptors, when 'knocked out' in mice (FIRKO mice) result in less visceral (around the internal organs) body fat than normal mice, even when fed the same number of calories and live almost 20% longer.
     Mice which underwent surgical removal of visceral body fat also experienced longer life spans as well as less kidney disease.
Visceral Body Fat

     Over-expression of  the enzyme PEPCK-C (phosphoenolpyruvate carboxykinase) in genetically manipulated mice resulted in a more than 50% life extension but these same mice could also run faster, ate 60% more, had 1/2 the body weight and 10% the body fat of control  (normal) mice.
     The major factor thought to be responsible for the longevity of the PEPCK-C minus mice was the low concentration of insulin in the blood of these mice which was maintained over their lifetime of hyperactivity.
     Other discoveries have also been made. In 2006, it was reported that scientists may have found a fountain of youth, a drug that appears to slow and even reverse the physical effects of ageing. In tests on nearly 400 men and women aged 65 and older, drug giant Pfizer's experimental pill significantly boosted levels of a hormone behind the growth spurt at puberty.

     Volunteers given the hormone stimulator called capromorelin experienced a 1.4 kilogram average increase in muscle mass. After six months of treatment, the volunteers showed a significant improvement in balance activities, walking 'heel to toe'; after 12 months, they were better able to climb stairs.
     An increasing human life span has been happening for quite some time. One hundred years ago, the average life expectancy in America was between 47 and 53. One hundred years before that, it was around 32. In the past 200 years we have almost tripled our expected life span which has increased from the low of 32 to today's high of 87 years.
     But just living longer is not really enough. Any person who has the desire to live a long life also wants a life in which he/she can stay young, fit and healthy. Otherwise that person may end up like Tithonus, wasted and withered, reduced to a mere shadow of himself, growing older and older and ever more feeble.
Tithonus, Wasted and Withered

     Today, some of the most profitable companies in the world are those which produce and market beauty and health pills and potions. Some of these 'youth treatments' may be effective; most are nothing more than a waste of money.
     Through the use of diet, genetic therapy, biotech, improved health care and lifestyle changes, life extension will continue to increase. But most of us will likely not be able to lean back and take a passive role, having certain of our genes 'knocked out' or manipulated or using drugs to restrict our calorie intake.
     What science is certain of today is that (too much) fat is bad, especially if it is 'on the inside' (visceral ie 'beer gut'); little or no exercise is a ticket to heart disease, diabetes (and probable shortened life); eating just enough (with a balanced diet) to maintain your ideal body weight (a type of  calorie 'restriction') is all that is needed; certain foods may be beneficial (grapes? red wine?) and others harmful (foods with high fat content).
     Certain activities are just plain bad for you (tobacco consumption, use of illicit drugs) and will likely be a direct cause of (early) death.

     But  proper living will not likely ever achieve what mankind has sought since before the beginning of history. A race to unlock genetic clues behind living to 100 and beyond is set to begin. A US team has announced that it will compete for the $10m Genomics X Prize. Genetic entrepreneur Dr. Jonathan Rothberg is entering the challenge to identify genes linked to a long, healthy life. Contenders will be given 30 days to work out the full DNA code of 100 centenarians at a cost of no more than $1,000 per genome.
     The race for long life will begin in September 2013.
     One last thought-provoking idea about how to extend life span, at least for males.
     Researchers in South Korea have analysed the genealogical record of eunuchs, looking at the lifespans of 81 eunuchs born between 1556 and 1861. The average age was 70 years, including three centenarians (the oldest reached 109 at time of death). It seems that castration had a huge effect on the lifespans of these Korean men who lived up to 19 years longer than uncastrated men from the same social class and even outlived members of the royal family.
Ancient Chinese Mural Depicting Eunuchs

     By comparison, men in other families in the noble classes lived into their early 50s. Males in the royal family lasted until they were just 45 on average.
     One thought is that male sex hormones such as testosterone, which are largely produced in the testes, could be damaging to the point that male hormones may indeed shorten life expectancy. The researchers postulated that the hormones could weaken the immune system or damage the heart. Castration would prevent most of the hormone from being produced, protecting the body from any damaging effect and prolonging lifespan.
     Click on the link below for an interesting TED talk by Aubrey David Nicholas Jasper de Grey.
     *Ageing and Immortality: subjects of research for the novel The Judas Kiss - Amazon Kindle.

Apocalypse 2012

     How many people think that this is the year of 'the end of the world, 'the rapture', 'the return of the messiah'? How many times has the human race thought of it before?

     There are legends, myths, confabulations about 'the end times' in nearly every culture that currently exists or has ever existed on this planet. And what demagogue (politician? religious leader?) wouldn't want to take advantage of that?
     *Apocalypse: subject of research for the novel  The Tao of the Thirteenth God - Amazon Kindle.