Can the Grim Reaper wait, please?

A timeless dream: eternal youth, unblemished by illness. The search for the font of immortality has taken a late 20th century turn into what seems like fantasy science. The basis of this search is the belief that if death cannot be staved off forever, human entropy can at least be postponed. Enter, genetics...

 
By S Sankarapandi
Published: Sunday 07 June 2015

Can the Grim Reaper wait, please?

-- (Credit: Rustam Vania / cse)HE HAD jet black hair when he quit the Oval Office 12 years ago, at unnerving variance with the network of age-lines on his face, wattles, dewlaps and all. But even then, his brain had already kicked off into the bottomless abyss of Alzheimer's disease. "I now begin the journey that will lead me into the sunset of my life," wrote Ronald Reagan in a recent open letter to his fellow Americans, revealing that his brain had begun to rot, irreversibly. He had survived terrible visitations upon his body: colon and skin cancer, prostate problems, even an assassin's bullet in the chest. What an irony it is that the man who once steered the world's most powerful nation now has no one in his driver's seat.

They say that Alzheimer's is the worst of all tortures -- watching memory and recognition fail, the synapses sputter into silence. Given a choice, it is a rare person who would not prefer Parkinson's disease or coronary heart diseases over the virtual brain death of Alzheimer's.

There will be 590 million oldsters(total estimated population?)-- 60 years and above -- by the fin de siecle, up from 200 million in 1950. Better healthcare services and falling birth rates will ensure that the rate of growth of the world's elderly will far surpass the rate of growth of the total population -- 60.5 per cent vs 37.6 per cent (over the 1980 figures). Thus, while the elderly might live longer -- in purely physical terms -- there will also be more cases of senile dementia, Alzheimer's, Parkinson's, et al.

To many, it's a frightening prospect. As it is, ageism -- prejudice against the aged -- is growing: the longer they live, the more they consume increasingly scarce resources. In a world where collective compassion went down the tube right after World War II, the old had no place to go but sanitaria during the youthquaking '60s. Only when the sanitaria filled up to bursting point, and subsidies to geriatric welfare projects and institutions gobbled up more money than the governments were willing to pay, were substantial grants channelised into gerontology, the scientific study of ageing. The focus suddenly shifted from treating illnesses associated with ageing to treating ageing itself.

The past 10 years have been a virtual gerontological goldmine. Scientists like Anthony Linnane of Australia's Monash University predict that it will soon be possible to increase the average human lifespan to 120 years.

But Methuselah doesn't have much to grin about. To a vast number, the very thought of extending the human lifespan -- often through methods termed theologically corrupt -- is disgusting. Their argument is that a longer lifespan will only elongate the period of declining health and geriatric loneliness in a world that questions the productivity of the old. Linnane, however, differs. "Our aim," he says, "is to make sure that the extra years are added to the youthful years, not to old age."

Happy thought, but how? Explains M S Kanungo(designation) of the Banaras Hindu University (BHU), Varanasi, whose basic research on the ageing process has earned him international repute, "Ageing is a natural and universal phenomenon which every organism undergoes. Once the cause of this process is discovered, it is possible to postpone the onset of old age."

FIRST CLUE
Molecular biologists, who use biochemical and genetic engineering techniques to unravel the process of ageing, recently got under the skin of the matter, so to say: they discovered that an individual's lifespan is ingrained in the genes. Individuals have their lives cut short by mutations or breakdown of these genes because of factors as diverse as unhealthy food habits, stress, pollution, heat and radiation.

The clue that genes determine lifespans came from Drosophila, the innocuous fruitfly, whose short life of 30 days allows scientists to observe the insect through many generations. By denying his flies the opportunity to breed early, Michael Rose of the University of California, Irvine, found that their lifespans could be increased by as much as a third in just 15 generations. The explanation is convoluted: during reproduction, molecules that repair DNA are activated to ensure that no errors occur when the genetic material of the parents is copied on to the progeny at the time of fertilisation. By postponing the reproduction process, the repair mechanism is kept in reserve to protect the genes from mutations that would otherwise have forced the flies to become old early.

Scientists have now moved on to identify specific genes and their mutations. The first of these genes, called age-1, tracked down by Thomas Johnson of the University of Colorado, has a key role in regulating the production of enzymes which mop up 2 toxic oxygen compounds -- hydrogen peroxide and superoxide -- that are released as byproducts during respiration. Johnson's experiments on C. elegans -- a microscopic worm -- showed that a mutation that disabled age-1 increased the production of these enzymes, prolonging the worm's lifespan by 70 per cent.

Linnane suggests strong links between mutations of the genetic material inside mitochondria -- the powerhouses present inside cells, where respiration actually takes place -- and the decline of physiological performance. "Since mitochondria is the place where the entire bioenergy is produced for the functioning of organs, is it not reasonable to presume a mitochondrial bioenergy decline in the ageing process?" asked Linnane at a recent international conference on biochemistry and molecular biology in New Delhi. According to him, some diseases of the aged such as Parkinson's and Alzheimer's are a result of bioenergy deficits, which can also lead to strokes.

The team of D Gershon of the Israel Institute of Technology at Haifa, Israel, has been studying genes that code for proteins called heat-shock proteins (HSP), which are produced by almost all organisms in response to sudden increases in temperature or stress. Experimenting with fruitflies, Gershon's team concluded that HSP genes gradually get deactivated with age, causing a reduction in HSP levels. Studies conducted by A Richardson at the University of Texas Health Science Centre confirms this mechanism. The scientists suggest that reactivating the genes may postpone the ageing process.

From experiments on rats and birds, Kanungo's team found that the expression of 3 proteins -- fibronectin, vitellogonin and ovalbumin -- decreases with age due to a change in corresponding gene promoters -- codes for the starting point of a gene. Says Kanungo, "By maintaining the levels of these promoters, it may be possible to maintain the activities of genes and postpone ageing."

Besides scientists who are on the look out for ageing genes, there are those who wish to hunt down and massacre the molecules that damage genes or DNA. Many scientists target oxygen free radicals -- the most reactive species of oxygen which assault cell membranes, proteins and genes.

Billions of free radicals are spewed out during the normal burning of food with oxygen in mitochondria to produce energy. Free radicals are not all bad -- they help fight disease and are harmful only when allowed to grow unchecked. Bruce Ames at the University of California, Berkeley, estimates that each cell's DNA gets hit about 100,000 times by free radicals every day. While the repair mechanism lets 1 per cent to go unmended.

The damage caused by free radicals may lead to many old-age diseases. Says Rameshwar Singh of the Jawaharlal Nehru University, New Delhi, "Lipid peroxidation is a process in which free radicals damage the fatty lipid molecules of cell membranes and leave them rancid. This is a major physiological change associated with ageing." Similarly, when blood sugar increases, free radicals anchor excess sugar molecules to the proteins, crosslink them and defuse them. Free radicals also react with cholesterol in blood vessels, leading to heart attacks and strokes.

Biochemists are looking for molecules that can capture the free radicals and postpone ageing. Their first choice is to use naturally available antioxidants like vitamins C. The late Nobel laureate Linus Pauling recommended a regular intake of 18 grams of vitamin C every day for a long and healthy life. Synthetic drug molecules such as deprenyl are also being explored for antioxidant properties. There are other chemicals like phenyl butyl nytrone or PNB which can capture free radicals and arrest their reactivity.Human trails on PNB are being planned and scientists claim it may be available for treatment ijn a few year.

HEALTHY AGEING
Food, nutrition and environment play a major role in the process of ageing, according to most scientists at an recent international symposium on gerontology in New Delhi. Fresh vegetables, fruits, nuts and cereals provide sufficient vitamins to overcome the free radicals while certain fatty foods and deep fried meat can serve as breeding grounds for free radicals.Smoking and environmental pollutants can help generate free radicals.

Physical exercise has also emerged as imperative for going down smiling. Studies conducted by a Stanford University team led by James Fries suggest that jogging and regular aerobic exercises help keep a person physically fit in the later years of life. Similarly, the mental faculties of physically active oldsters tend to be sharper than in sedentary members of the same age group, according to a report published in January this year by C Cotman and his colleagues at the University of California.

Another promise for extended youth, although clouded in controversy, is growth hormones -- biochemicals secreted naturally by pituitary glands. According to Daniel Rudman, a US researcher on human growth hormones at the Veterans' Affairs Medical Center in Milwaukee, Wisconsin, people between 60 and 90 go through a phase called somatopause, after which growth hormones tail off dramatically, similar to the menopause. After somatopause, the lean body mass reduces while fat mass increases. This finding convinced Rudman to treat elderly people with growth hormones, and in 1990, he demonstrated an increase in lean tissue and reduction of fat in 21 healthy men aged over 60.

EQUIPPED TO KILL
Subsequently, in 1993, a Swedish team led by Bengtake Bengtsson at the University of Gothenburg reported that growth hormone-deficient adults who were treated with the hormone lost 30 per cent of their abdominal fat but only 13 per cent of peripheral fat. Douglas Crist, a physiologist at the University of New Mexico showed that the anatomies of people armed with the hormone are better equipped to kill cancer cells.

Another anti-ageing pill which hit the news in January this year is dihydro-epi-androsterone (DHEA). A hormone secreted in large quantities by the adrenal glands at about 20 years of age, DHEA declines rapidly in over time. Samuel Yen at the University of California at San Diego found a correlation between low DHEA levels and death from cardiovascular diseases. The results of 2 separate trials on volunteers, conducted by Yen and French scientist Emile Baulieu, indicate potential applications of DHEA as an anti-ageing pill. But scepticism runs free at the National Institutes of Health and other medical centres in the US.

Rudman has already reported several side-effects of growth hormones: abnormal rise of blood sugar, enlargement of breasts and increased pressure on the nerves. Says Rudman, "We need many years to establish this treatment to be safe, logical and effective."

Other researchers are even more pessimistic. According to Marc Blackman, who heads gerontology at the Francis Scott Medical Center in Baltimore, big claims about growth hormones are yet to be substantiated. Andrew Hoffman at the Veterans' Affairs Medical Center at Palo Alto in California asks, "Does it make sense to give such a powerful hormone to people who are basically healthy unless the benefits are shown to outweigh the risks?"

A legal anti-ageing therapy seems nowhere near, since these issues need to be addressed before commercial exploitation of any new finding. "The uncritical adoption of the most recent therapies for elderly patients might sometimes do more harm than good," said British physician Q F W James at the World Gerontology Congress held in Budapest in July 1994. The congress placed greater emphasis on quality of life for the elderly rather than its duration. "It would yield benefits to society as the old population represents enormous intellectual potential," said Edit Beregi, president of the Congress.

Studies conducted worldwide indicate that retirement and loss of income and status lead to stress and frustration. Says P V Ramamurti, head of the Centre for Research on Ageing at Sree Venkateshwara University, Tirupati, "More than 2/3rds of elderly people in India are poor, and India cannot afford state care. Only income generation schemes could make them contribute their knowledge meaningfully. Family ties should be strengthened to alleviate feelings of loneliness."

It is many years still to paradise.

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