Does Mother Nature Have Some Rejuvenation Tricks Up Her Sleeve? 

May 24, 2004

Is It Necessary to Fully Understand Aging in Order to Ameliorate It?
    I would like to make some "meta-observations" about this topic.
    A scientific model of the aging process is certainly desirable, and in the course of time, I imagine that we'll have it. However, with respect to the engineering problem of arresting or reversing aging, I'd like to present a parable.
The Engineering Approach to a Longer-Lived Car
    Suppose that Stone Age savants were trying to understand why 1970-vintage U. S. cars wear out. They might have come up with various kinds of wear-and-tear theories about it, and about why wearing out was inevitable when a car reached a certain number of miles. And we might suppose that their theories would have been correct as far as they went. What (we'll assume for the purposes of this parable) they wouldn't have known would have been that Detroit had a policy of "planned obsolescence", deliberately designing U. S. cars so that parts would wear out at about 70,000 miles.. until they encountered a  Mercedes diesel or a Rolls Royce. Then it would have been evident to them that, although their theories about the wearing out of automobiles were qualitatively correct, and were even quantitatively correct insofar as U. S.-made cars were concerned, their models wouldn't quantatively predict the lifespans of the Mercedes, the Rolls-Royce, and other cars that were not manufactured in accordance with the U. S.' policy of planned obsolesence. So if you had wanted a longer-lived car, you wouldn't have had to understand the intricacies of wear, and of detailed remedial techniques. All you would have needed to do would have been to buy a Mercedes or a Rolls-Royce. And the higher-level policy decision of planned breakdown would have been the key to understanding why U.S.-made cars broke down when they did.
    In other words, there would have been different levels of explanation. There would have been the highly technical explanations about the wear-and-tear process itself, and assiduous researchers might have devised an accurate model of this process. At the same time, there would have be a higher level of explanation: the fact that U. S.-built cars were deliberately designed to wear out at a certain mileage in order to encourage them to buy a new car from the same manufacturers.
Applying This to Aging:
    I want to propose that, just possibly, a similar situation exists with respect to aging.
    The question here is that of whether or not Nature is trying to secure the longest feasible lifespan for a given species (such as humans), and that it would be very difficult to effect major increases in human lifespan, or to rejuvenate older humans.
(1)    In 1998 or early 1999, researchers at Advanced Cell Technology took 6 somatic cells from a very old cow and inserted them into 6 enucleated bovine ova. Presumably, the 6 somatic cells were denatured with the damages of old age. Yet somehow, they were completely rejuvenated after they were inserted into the presumably-young ova. From them grew six  normal,  brand-spanking-new calves (which are now 5-year-old cows). So how did this happen? What about advanced glycation end products? Age-induced genetic damage? Cross-linking? A follow-up study by Jerry Yang at the University of Connecticut verified the rejuvenation effect  in 2001. Somehow, these defects aren't present in the new calf cells that were produced by the original fertilized egg cells. And total rejuvenation of sperm and egg cells seems to happen whenever fertilization takes place. (Until recently, it was thought that human ova are all created before birth, but it's now known that additional egg cells may be manufactured throughout a woman's childbearing years.) This argues to me that Nature routinely rejuvenates zygotes before first-mitosis. How does Nature rejuvenate cells immediately after reproduction? (I realize that I'm tacitly assuming that rejuvenation....  viz., restoration of telomere lengths...  occurs immediately after fertilization rather than during embryonic development, and this may be wrong.) 
    Stem cells are also rejuvenated.
(2)    Rockfish come in a variety of species with lifespans ranging from 12 years to more than 100 (and probably, to more-than 200). Furthermore, the longest-lived rockfish, the rough-eyed rockfish, shows no signs of senescence. (Of course, this may simply mean that we haven't seen old enough rockfish to see the effects of aging among them.) A similar situation exists with the red sea urchin. Sea urchins have varying lifespans, with the red sea urchin thought to live more than 200 years, and show no detectable senescence. Clearly, it's possible for different species in the same genus to have drastically different rates of aging. This also suggest to me that it's not terribly difficult to crank up lifespan, and in the case of the red sea urchin and the rough-eyed rockfish, to actually achieve negligible senescence... i. e., virtually zero aging.
(3)    Bowhead whales (Bowhead Whales May Be the World's Oldest Mammals) and probably some other whales have lifespans that exceed 200 years.
(4)    Lifetime caloric restriction, in the first gene-chip study of the genetic effects of caloric restriction conducted by Weindruch and Prolla in 1999, reduced or eliminated the changes in about 70% of the aging 113 genes that they identified in their landmark study. 
    Dr. Stephen Spindler announced in 2001 that caloric restriction very late in life produces about 70% of the genetic anti-aging effects that are caused by lifetime caloric restriction, engendering perhaps 50% of the reduction or elimination of the changes in the genes that change with aging. (This is recent work, and these are recent results.) In other words, caloric restriction produces partial rejuvenation--partial in two ways. First, the organism isn't taken back to the moment of conception or close to it. Second, not every function is affected. Still this suggests to me a biological program that responds to hard times with partial rejuvenation.
(5)    As the recent Washington University study showed, can be partially rejuvenated (only partial in terms of years and in terms of functions) by caloric restriction later in life. 
(6)    The antagonistic pleiotropy model of cancer has Nature trading a cancer-resistant youth for much-higher  risks of cancer in old age. Aggressive apoptosis in youth speeds cell-line reproductive exhaustion, and leads to aging and concomitantly high levels of cancer in old age. The suggestion is that Mother Nature has gone all-out to give us the low rates of cancer that allow us to reach old age, and would find it difficult to materially improve upon our cancer resistance without accelerating our rate of aging. Mother Nature has already optimized this tradeoff. 
        However....
        Consider the case of the blue whale. Blue whales have lifespans that are approximately equal to ours (and may even have longer lifespans, as we're just now learning about the bow whale). But blue whales have something like 1,000 times as many cells as we do, and given the same biological defenses against cancer, the risk of cancer should be proportional to the number of cells in an organism. How come blue whales don't have 1,000 times the cancer risk that we do?
        The only conclusion I can reach is that Mother nature isn't telling us everything. She has some tricks up her sleeve that we don't yet know about.
Conclusion:
    Reviewing this evidence, I conclude that there may be natural ways to effect rejuvenation without understanding the details of how this works. To draw a parallel, if we had waited until we understood the thermodynamics and kinetics of boiling water before we tried it, it would have been a long wait. (We still couldn't calculate very accurately how long it would take fried egg to cool. We would need a certain amount of input data to arrive at a rough estimation.)

Possible Implications for Research 
    The few of my "health indices" that were measured in February showed substantial improvements over all their prior values. The numbers cited in the Washington University study show most of the changes occurring by the time the participants had been calorically restricted for a year. The further changes to the present time appear to me to be roughly proportional to the further decline in average body mass index among the 18 participants, rather than to having been calorically restricted for a longer period of time.
    It may fairly be argued that these indices aren't biomarkers of aging per se. They need to be confirmed with other biomarkers that are more intimately associated with aging. However, the central role of cardiovascular competence in longevity intimates that these biomarkers are at least consistent with increased longevity. The 40% decrease in intima media thickness seems to me to be something beyond the mere side effects of slimness. I suspect that a full panel of aging biomarkers will confirm what this restricted set of cardiovascular indices suggests: that CR fairly rapidly produces substantial improvements in the subset of aging biomarkers that are modulated by calorie restriction.
    If so, then, using human subjects, some age-reversal strategies could be assessed within a period of months.