Slowing Down Life’s Clock

Decades of research on aging are beginning to pay off, although it doesn’t mean that increasing longevity is a pill away, writes T.V. Jayan

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It’s been a decade and a half since Cynthia Kenyon genetically tweaked roundworms to expand their lifespan to twice the normal length. Science has not been able to uncork the fountain of youth yet, but the jump-start Kenyon and her colleagues at the University of California, San Francisco, gave to longevity research    by making the wrigglers, through the manipulation of a single gene, live for 40 days instead of 20  has helped resolve many mysteries surrounding the issue of ageing.

The latest in the list is the revelation that the ubiquitous molecule, insulin, comes in the way of a prolonged lifespan. Another independent study points to the benefits calorie restriction has on longevity by making nearly starved roundworms live 40 per cent longer than their well-fed peers.

Too much insulin ” a hormone that tells our cells to use sugar from the bloodstream, thus helping us to avoid metabolic complications that lead to diseases such as diabetes  in the brain may not be a good sign, said a team of researchers from the Howard Hughes Medical Institute in Boston.

By saying so, the researchers  led by endocrinologist Morris White  scientifically reinforced what every mother might tell her child: Eat a good diet and exercise; it will keep you healthy.

The researchers, who sought to understand the role of the insulin-signalling pathway in extending lifespan, found actually the opposite of what most scientists and clinicians believed. Because, according to White, most would find it difficult to accept the idea that insulin can reduce lifespan. This signalling pathway of insulin governs growth and metabolic processes in cells throughout the body.

Tests on lab mice showed that when both the copies of a gene responsible for insulin signalling — called Irs2 — were knocked off in the brain but retained in cells in other organs, the animals lived about six months longer than usual. This is nearly 18 per cent more than the animal’s normal lifespan.

This even though the genetically modified mice were overweight and had higher blood insulin levels. To the scientist’s  surprise, they became more active with age and their glucose metabolism resembled that of younger mice. Besides, their brains showed higher levels of superoxide dismutase, an antioxidant enzyme that protects cells from damage caused by highly reactive chemicals called free radicals.

So diet, physical activity and lower weight keep one’s peripheral tissues sensitive to insulin. This reduces the amount and duration of insulin secretion required to keep glucose under control when one eats. This way, the brain is exposed to less insulin. And since insulin turns on Irs2, the lower the insulin, the lower the IRs2 activity, White observed. The findings were reported in the July 20 issue of the journal Science.

While White’s team pointed to a balanced diet and keeping fit as the recipe for a long life, Andrew Dillin of the Salk Institute of Biological Studies in the US — who had co-authored several papers on ageing with Kenyon — found a gene in roundworms that specifically links calorie restriction to longevity. Interestingly, an Indian scientist, Kalluri Subba Rao, arrived at a similar conclusion more than a decade ago by studying undernourished people and comparing them with those who ate a normal diet.

Dillin and his colleagues in a way cracked open the black box of how persistent hunger increases longevity. “After 72 years of not knowing how calorie restriction works, we finally have genetic evidence to unravel the underlying molecular programme required for increased longevity in response to calorie restriction,” he said.

What is significant about his work is that the gene they identified, pha-4, is independent of those involved in the insulin pathway, which has been the focus of most longevity research so far. The loss of only this gene — which encodes for the protein PHA-4 — negated the lifespan-enhancing effects of calorie restriction in worms. So the scientists did the opposite — that is, overexpress the pha-4 gene in the worms. It worked, and the worms lived as much as 40 per cent longer.

Human beings, says Dillin, possess three genes similar to the pha-4 gene of worms, all belonging to what is called the Foxa family. These three genes play an important role in the development and later, the regulation, of glucagon — a pancreatic hormone that, unlike insulin, increases the blood sugar concentration and maintains the body’s energy balance, especially during fasting.

Subba Rao, an emeritus professor at the University of Hyderabad who in 1996 reported the benefits of diet restriction on ageing, agrees. Down-regulating glucose signalling has several positive effects, longevity being one of them. “The body is programmed to metabolise, say, one tonne of sugar over a lifetime. In how much time one does it is entirely up to that person,” said Subba Rao, coordinator of the university’s Centre for Research and Education in Ageing.

Concerted efforts over the last 15 years in the biology of ageing are paying off, although it doesn’t mean that increasing one’s lifespan is a pill away. But scientists are already taking the research to the next level: studying the proteins involved in the process. Examining the process of ageing from the protein perspective may lead to therapeutic methods of delaying ageing in the not-so-distant future, provided the scientists repeat in humans the feats they have achieved in worms and mice.

Last week, a team of researchers at the Scripps Research Institute in La Jolla, California, identified some 86 proteins whose abundance varied in mutant round worms as compared to normal ones. While 47 of the proteins were more abundant in worms that were genetically altered to live twice longer, another 39 were less abundant than in the controls. “Proteins are harder to study but they are closer to the enzymatic processes involved,” John Yates, who led the study, told KnowHow.

Enzymatic processes are the closest one can get when it comes to therapeutics as they are part of the bodys routine biochemical processes. It is for the same reason that many new-generation drugs today have enzymes as their key component.

Source: The Telegraph (Kolkata, India)

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