Sunday, October 19, 2008

Of Wine, Worms & Mice: Dreams of Immortality...

Longevity Dreams
Jeanne Calment of France, once the oldest documented human in the world died at age 122 years in 1997. Others like some Okinawans routinely lived to 100 years and beyond.

Some geneticists such as Tom Johnson, of the University of Colorado, thinks people could one day live to 350 years old, spanning the ages like Methuselah and the other biblical patriarchs.

As far as we can imagine, most of us do fear dying, and nearly all of us yearn for a longer life. Yet, most if not all of us don't have any concrete ideas as to how long we would like to live, or exactly when we would like or choose to expire
that ultimate certainty of eclipsing this world, is inherently unascertainable and yet petrifyingly spooky.

From earliest moments when he first became a sentient being, Man had always been a dreamer.
Cogito Ergo, Sum ("I think, therefore I exist") so said Descartes.

By realising that he had a mind to begin with, and with independent thoughts to wit—thoughts that transcended and more often than not, exceeded or supervened beyond bestial mundane concerns—he began to become self-aware...

These self-aware thoughts differentiated him from other creatures, whose immediate concerns initially appeared to be just staving off hunger, finding food, feeding, procreating and surviving, i.e. trying to keep alive, gathering edible food, hunting, including escaping from other predators... Later, he embarked on growing food, domesticating and harnessing wild animals, etc.

Food and shelter must have been sporadic and uneven, then. Hunger and the continual search for available food sources would also serve as potent forces for man to explore beyond his immediate locale and habitat. With more extremes of temperature and climatic shifts, these would have been very difficult and severely hard times.

Eating sparingly and just enough would have been the innate habit of early man. Surviving extremes of famine and privation would have pre-selected only the hardiest, those with the so-called starvation genes to withstand the ultimate...

Hunger would also have been one critical inherent instinct for survival, for action, for living. Curiously, hunger (caloric restriction, near-starvation) has now been found to be an extremely powerful determinant for a longer life!

Death and dying must have intruded into his emerging but burgeoning consciousness very early on, as he grappled with those around him who had perished from unexplained sickness or wounds, inflicted from fights among themselves, or from more vicious predator animals out there.

One wonders too, when man first started to think about maintaining or even extending his own life, first as a natural instinct to keep and stay alive, and later perhaps to forcefully guard his tenacity to not only be alive, but to control his destiny and those of others around him.

Many if not most children who were born then, would have been stillborn, or die sooner than they are wont to, in those days of antiquity... We speculate too, if ancestral man ever thought too seriously or deeply about his progeny, and whether he ever saw this as an extension of his very finite and transitory life.

That he probably cared enough has been intuited from unique burial rites of several children that have been discovered in widely different locales and separate sites. But mounting evidence of possible cannibalism somewhat tarnishes our more benign linkages and haunting endearment to our ancestral lines of hominids, very early 'humans'.

Once language and communication had advanced beyond simple guttural sounds and hand-signs, abstract pictographic words emerged and primal languages flourished, which during dusk, gloaming campfire moments serve as quiescent times for communication, story-telling allowing imaginary thoughts to be explored, and passed along... Survival must then be the be-all and end-all of early hominid lives...

It is then quite fantastic to ruminate that by the end of the nineteenth century, just a mere century ago, man's average life expectancy was hovering around 50 years, this meagre survival coming in the wake of some tens of thousands of years since his awakening into modern man.

One hundred years hence, and we are now regularly expected to live 3 scores and ten i.e. some 70 years, with many societies now approaching beyond 80 years or more. But although most biblical exhortations imply that man's longevity is 3 scores and ten, the Genesis appear to place a cap of 120 years on man's wandering spirit:
"And the Lord said, 'My spirit shall not strive with man forever, for he is indeed flesh; yet his days shall be one hundred and twenty years.'"
~ Genesis. 6:3

Moderate Calorie Restriction—the pha-4 Gene
Aside from moderate calorie restriction (some 30 to 60% fewer than necessary), scientists have now also found some genes which appear to be linked to longevity, particularly genes which are involved in the lengthening of telomeres.

As cells go through cycles of rebirth and regeneration these DNA telomeres become progressively shortened until they no longer function efficiently to prevent ageing and thus facilitate programmed deaths (also called apoptosis), i.e. cell senescence. By blocking these telomere-shortening enzymes, and inserting genes which lengthen these telomeres, it may be possible to stall the ageing process.

A whole host of genes have now been linked to extending longevity among animals. Many of these genes carry inexpressive monikers such as: daf-2, p66shc, ctl-1, Lamin A, SIRT-1. Others are more whimsical like age-1, clock, Methuselah, and INDY—for "I'm Not Dead Yet"!

Of more interesting note, a recent study done with the nematode worm species Caenorhabditis elegans showed that there is a correlation between lengthening telomeres and a longer lifespan. Two groups of worms which produced different amounts of the protein HRP-1, were studied. The amounts of protein HRP-1 produced is determined by the expression of a 'starvation gene' which has been identified as the pha-4 gene.

The team from the Salk Institute for Biological Studies, found that worms that had their pha-4 genes removed showed no enhanced longevity while on the restricted diet. But they discovered that the opposite experiment—over-expressing levels of pha-4 in the worms—increased longevity when on the restricted diet. It appears that this pha-4 gene-expressed increase in HRP-1 resulted in telomere lengthening in the mutant worms. The worms with the longer telomeres lived 24 days on average, about 20 percent longer than the normal worms.

Mammals, including humans, possess genes that are very similar to the pha-4 gene. Pha-4 appears to be the primordial gene that helped animals overcome stressful conditions to live a longer time through extreme dietary restriction conditions, i.e. times of famine or hardship in hunting/feeding, etc.

The Wine Connection—Sirtuin Activators

Hoping Two Drugs Carry a Side Effect: Longer Life

Living Forever: The Longevity Revolution

Lately too, the New York Times carried a lead article on new drugs called sirtuin activators (these activate an enzyme called sirtuin). "The basic theory is that all or most species have an ancient strategy for riding out famines: switch resources from reproduction to tissue maintenance. A healthy diet but with 30 percent fewer calories than usual triggers this reaction in mice and is the one intervention that reliably increases their life span. The mice seem to live longer because they are somehow protected from the usual diseases that kill them."

Interestingly, these sirtuin activators which appear to have the property of simulating the famine reflex, have now been linked to some powerful antioxidants. These appear to be modifiable by using flavonoids first identified from red wine i.e. resveratrol. Resveratrol has long been known to be useful in extending life of mice, which had been fed huge doses. SRT501, a novel formulation of resveratrol has been found to be 5 times as potent as resveratrol, in raising blood levels of the active component, discovered by Dr Sinclair who has since sold his start-up company Sirtris, to GSK (GlaxoSmithKline).

In mice testing, resveratrol has doubled muscular endurance, lowered LDL, the bad form of cholesterol, protected against various bad effects of a high-fat diet and suppressed colon cancer. Another study (in Cell Metabolism, July 3, 2008) by Drs. Sinclair and de Cabo of the National Institute on Aging, found that resveratrol given to ageing mice reduced their cataracts, strengthened their bones, improved coordination and enhanced their health in several other ways. Yet despite their better health, the mice lived no longer than usual. So there still remains uncertainty as to the real benefits at this juncture of research.

Another Sirtris drug under development is a small synthetic chemical that is 1000 times more powerful than resveratrol in activating sirtuin, thus it can be given at a much smaller dose. Safety tests in people have just started, with no adverse effects so far. Clearly, this compound may be more potent. So it appears that perhaps more consistent life-extending properties may yet be replicated in humans...

It is hoped and estimated that sirtuin activator therapy may extend life by some 5 to 10%... However, GSK's spokeperson Dr Vallance states that the goal is not the extension of human life span; rather “the prolongation of health is the aim.”

One of my longer-lived patients, a Dato Chin (who died recently at 95 years) always advised that he ate sensibly and moderately: "eat until you're about 70% full, then stop; it's healhier," he said this was passed down by his father and his forebears before him. Perhaps, these people know something that we have only now begun to understand better.

Notwithstanding the advances in longevity science of worms and mice, as of now, it appears that we still have to continue to dream of immortality.
.. Perhaps, the easiest and safest approach to aspiring for a longer life is quite simplejust eat less, and live longer!


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Dr D Quek said...

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