Fight Aging!

Molecular biologist Derya Unutmaz (who maintains Biosingularity, and who was interviewed not so long ago by Attila Chordash of Pimm) made a few comments via the Gerontology Research Group mailing list on the topic of the recent New Yorker piece "The Way We Age":

There are several misconceptions early in the article in my opinion, see my comments below, which are mostly meant for discussion purposes.

These findings notwithstanding, scientists do not believe that our life spans are actually programmed into us.

I am wondering who are these scientists why they do not believe that our life spans are actually programmed in us?

After all, for most of our hundred-thousand-year existence­ - all but the past couple of hundred years ­- the average life span of human beings has been thirty years or less. (Research suggests that subjects of the Roman Empire had an average life expectancy of twenty-eight years.) Today, the average life span in developed countries is almost eighty years. If human life spans depend on our genetics, then medicine has got the upper hand. We are, in a way, freaks living well beyond our appointed time.

This is gross misconception. The reason why the average life span was so low was because most of the deaths occurred during childhood and through infections during adulthood. If one corrects for the infection survival and looks at life expectancy at older age, there has only been about 6-8 years increase in overall life extension in the last 100 years. Thus, the data strongly argues for biological program of aging, and that at current time we are not yet freaks living much beyond our appointed time, just that many more of us reaching the near maximal set program.

So when we study aging what we are trying to understand is not so much a natural process as an unnatural one. Inheritance has surprisingly little influence on longevity. James Vaupel, of the Max Planck Institute for Demographic Research, in Rostock, Germany, notes that only six per cent of how long you'll live....

This is not correct. The most comprehensive Danish twins study found that the genetic factors account for about 25% of longevity, which I think again greatly underestimates the biological genetic program because the life styles vary greatly even between identical twins. If genetically identical twins have the exact life styles, they appear to live remarkably to about the same age, again arguing for biological program.

If our genes explain less than we imagined, the wear-and-tear model may explain more than we knew. Leonid Gavrilov, a researcher at the University of Chicago, argues that human beings fail the way all complex systems fail: randomly and gradually. As engineers have long recognized, many simple devices do not age. They function reliably until a critical component fails, and the whole thing dies instantly. A windup toy works smoothly until a gear rusts or a spring breaks, and then it doesn't work at all. But complex systems­ - power plants, say­ - have to survive and function despite having thousands of critical components.

Again I would argue that wear-and-tear model is gross oversimplification. If the simple wear-and-tear model was true for complex biological organisms then one would not expect wild differences in lifespan of equally complex organisms such a mouse (2 years), human (100 years), Bowhead whales and turtles (200 years), or some plants/trees (1000s of years). This also contradicts with an earlier paragraph in the article.

While the engineering analogies made by some appear intuitive or attractive, they forget the biological systems are autonomous in that they have built in repair and control mechanisms and far more flexibility then material systems. When a gear of a car breaks down or rusts, that car can not repair itself or install a new gear, whereas our bodies perform these operations every day both on the cellular and organismal level. This is a fundamental distinction.

Engineers therefore design these machines with multiple layers of redundancy: with backup systems, and backup systems for the backup systems. The backups may not be as efficient as the first-line components, but they allow the machine to keep going even as damage accumulates. Gavrilov argues that, within the parameters established by our genes, that's exactly how human beings appear to work. We have an extra kidney, an extra lung, an extra gonad, extra teeth.

Mice and humans have exactly the same number of organs and appear to have the same backup systems, why is it that there is a 50 fold difference in their lifespan?

It happens in a bewildering array of ways. Hair grows gray, for instance, simply because we run out of the pigment cells that give hair its color. The natural life cycle of the scalp's pigment cells is just a few years. We rely on stem cells under the surface to migrate in and replace them. Gradually, however, the stem-cell reservoir is used up. By the age of fifty, as a result, half of the average person's hairs have gone gray.

So what if our stem-cell reservoir was never used up? Can we have non-gray and full hairs indefinitely or much much longer? That is to say if the code was written such that stem cells continued renewal for 200 years instead of 50.

Inside skin cells, the mechanisms that clear out waste products slowly break down and the muck coalesces into a clot of gooey yellow-brown pigment known as lipofuscin. These are the age spots we see in skin. When lipofuscin accumulates in sweat glands, the sweat glands cannot function, which helps explain why we become so susceptible to heat stroke and heat exhaustion in old age.

What if the mechanisms that clear out the waste products don't break down or rather stop working? That is if the genetic code was such that garbage collectors continued to do their job.

The eyes go for different reasons. The lens is made of crystallin proteins that are tremendously durable, but they change chemically in ways that diminish their elasticity over time­hence the farsightedness that most people develop beginning in their fourth decade. The process also gradually yellows the lens. Even without cataracts (the whitish clouding of the lens caused by excessive ultraviolet exposure, high cholesterol, diabetes, cigarette smoking, and other unhelpful conditions), the amount of light reaching the retina of a healthy sixty-year-old is one-third that of a twenty-year-old.

This could be one of those conditions that really is due to wear-and-tear, and needs to be regenerated or replaced completely.

I spoke to Felix Silverstone, who for twenty-four years was the senior geriatrician at the Parker Jewish Institute, in New York, and has published more than a hundred studies on aging. There is, he said, "no single, common cellular mechanism to the aging process." Our bodies accumulate lipofuscin and oxygen free-radical damage and random DNA mutations and numerous other microcellular problems. The process is gradual and unrelenting. "We just fall apart," he said.

I would say "it's the genetic program stupid" :)

I think there are gray areas where structure and process as defined by our genes ends and wear and tear picks up; I would present the whole as a case of wear and tear acting on a self-repairing system with certain defined characteristics. The end result is complex, highly varying between individual circumstances, but much more consistent over statistically significant (i.e. large) groupings of similar genes and lifestyles.

One of the fundamental and most important debates amongst those working on the development of longevity medicine is this: do we give priority to changing our program of operation (by, say, manipulating gene expression, altering our genes, or otherwise shifting the activity of proteins in our body), or do we attempt to fix up the wear and tear in the present program of operation. Discussion of the sort Unutmaz engages in above are far from academic: research, development, fundraising and education is taking place today. The foundation of the next decade of research is being laid right now - the effectiveness of that research will mean the difference between life and death for uncounted millions.

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