Reversibility of Caloric-Restriction Rejuvenation?

May 17, 2004

Caloric Restriction May Partially Rejuvenate, But...
    ...But it supposedly disappears once you quit caloric restriction. This is consistent with the idea that organisms respond to adversity by diverting resources from growth and reproduction to repairing and refurbishing the organism, and then reverting to a high-burn-rate reproductive mode once prosperity reappears. However, if this involved the repair of, viz., genetic damage or collagen, one wouldn't expect genetic repairs to be "unrepaired" in a matter of a few months after the repairs had been made.
    It is the rule rather than the exception that, for example, an increase in HDL with exercise will disappear after the exercise ceases, so there's certainly a precedent  Still, it's hard to see how genes can be partially or wholly reset and repaired (if that's actually happening) without some permanence attaching to these changes. Also, how do the partially rejuvenated genes remember to what age they're to be reset?
Are These Genes Simply Temporarily and Dynamically Altered?
    It would be plausible to suppose that these genes aren't actually being reset to more-youthful states, but are being dynamically held in a rejuvenated state in response (directly or indirectly) to the hormetic mimetic (e. g., resveratrol) or its corresponding sirtuin that's being continually produced in response to some stress (such as a shortage of food) on the organisim. In that case, once that stress and its corresponding mimetic signal disappears, the genes would revert to their former settings, as though they were spring-loaded.
The Washington University Study of 18 Calorie-Restricted "Longevinauts"
    To give a specific example, with the 18 volunteers texted in the Washington University study, there were  substantial improvements in a bevy of atherosclerotic and other risk factors after the calorically restricted participants had adhered to their regimens for a year. (Note that these volunteers ranged in age from 35 to 82, with an average age of 58. They had been on a calorie-restricted diet for 3 to 15 years, for an average of 6 years.) For example, their fasting glucose levels dropped from something like averages of 94 or 95 mg./dl to 81 mg./dl. Their total cholesterol dropped from an average of 194 mg./dl to an average of 157 mg./dl. Their HDL values rose from an average of 43 mg./dl to an average of 65 mg./dl. Presumably, if they were to go off their calorie-restricted diets, within no more than a year, these risk factors would assume higher values. However, it's interesting to ask: what would happen if they remained at their lower weight levels (an average Body Mass Index of 19.5)? Presumably, their atherosclerotic risk factors would end up somewhere in between their calorie-restricted values and the values they had when they weighed 20% more than they do at a BMI of 19.5.
How Much of These Changes Are Simply a Result of Weight Loss?
    It's also interesting to inquire after what fraction of these changes are simply a result of weight reduction rather than of calorie restriction. Both systolic and diastolic blood pressures fall by about 1 mm. of Hg for every kilogram of weight lost. However, it's hard to imagine an increase of 20 mg./dl. of HDL simply through weight loss.
Meanwhile, Back at the Life Extension Foundation...
    The latest edition of Life Extension magazine says that the Life Extension Foundation is sponsoring a study of metformin on the lifespans of 40 mice. Of course, this will take several years to complete. The Life Extension Foundation is also working with Harvard Medical School (David Sinclair?) and Critical Care Research to find forms of resveratrol to test, and "will probably also test one or two analogs of resveratrol developed at Harvard".
    The Life Extension Foundation observes that the ability to screen drugs for anti-aging effects in only two to four weeks in mice is an enormous breakthrough. (I would observe that relatively safe agents like metformin can be screened in humans in no more than four months to see whether they yield the kinds of changes that caloric restriction provides. I base that on the changes in my bloodwork from September to February.)