Thoughts Regarding the State of the Art in the Retardation and Reversal of Aging

June 1, 2004

The Caloric-Restriction Response is Response the Only Known Way to Increase Species-Specific Maximum Lifespans 
    Notice that I've worded this "the caloric-restriction response" because the diabetic medicine Glucophage (metformin) also seems to evoke many of the age-ameliorating effects of caloric-restriction.
    Caloric restriction consists of dieting down to slim and trim, and then 
Caloric Restriction Alters (in a Youthful Direction) Changes in Age-Affected Genes
    As Weindruch and Prolla, and Dr. Stephen Spindler, Dr. Joseph Dhahbi, Patricia Mote, et al, have shown, caloric restriction is accompanied by a partial reversal of most of the genetic changes that occur with aging. However, when caloric-restriction is discontinued, the effects of caloric restriction upon lifespan are at least somewhat reduced. I asked two weeks ago in a write-up, "Are These Genes Simply Temporarily and Dynamically Altered?", how the genes involved in aging and caloric restriction were set back to their old values corresponding to the age of the organism. What calender does each individual gene use to know how to reset itself? 
Examining and Comparing the Genetic Changes During Fasting to the Genetic Changes During Caloric-Restriction
    A February, 2004, paper (pdf) might offer clues to this riddle. It compares the gene changes that occur during starvation with the gene changes taking place during caloric restriction, and suggests that the gene changes associated with caloric restriction are a watered-down version of those expressed during starvation. (Starvation would seem to be the ultimate but unsustainable extreme form of caloric restriction.) This 61-page treatise identifies the gene changes that occur in up to 269 genes among 20,000 liver genes when mice are forced to fast 24 and 48 hours compared to mice fed sugar-water (40% sucrose, 10% glucose) for 48 hours. 
    If I use a 30-to-1 conversion factor from mouse-months to man-years, I get "fasting" periods of 30 days and 60 days for these mice. No wonder the paper refers to these "fasts" as starvation!
    One point that I've learned from this paper is that 
Fasting Must Be the Rule Rather Than the Exception in Animals
    Food shortages must be the rule rather than the exception in the animal kingdom. Animals must typically have to endure fasts of varying lengths when food isn't immediately available, and it seems that there is a genetic program in place to accommodate this. This study shows that for the mice on sugar for 48 hours, 62 genes showed alterations; for those fasting for 24 hours, 131 genes were affected; and for those fasting for 48 hours, 269 genes were altered. 
    Some genes involved in metabolizing stored body fat were up-regulated during fasting, while some genes moderating fat synthesis were down-regulated. 
Catalog of Caloric-Restriction-Affected Genes
    The paper also lists the various genes that are altered by 48-hour fasting, and gives information concerning their known functions. 
Volatility of These Genetic Changes
    The essence of such studies is that organisms are genetically programmed at the cellular level to make adjustments when food runs low or runs out, probably signaled through low blood sugar (or maybe low insulin) levels over an extended period of time. Once the period of fasting is over, these genes presumably return to their "plump and prosperous" settings. This suggests (at least to me) that these genes can regress from their current "age-settings" by a amount proportional to the degree of caloric restriction or other stressor that the organism is currently experiencing. For example, for an age-affected gene that is set to, let's say, an age of 18 months in an 18-month-old mouse, caloric-restriction can improve certain survival functions to the tune of 3 months worth of hardship-contingent improvements with 25% caloric-restriction, and with 6 months worth of hardship-contingent enhancements if the mouse is facing 50% caloric-restriction. Once the crisis has passed and the mouse is dining on caviar, the genes (which happen to be among those that change with age) revert to their 18-month-old (or maybe by now, 19-month-old) states.
    Of course, this leaves moot just how aging is clocked month-by-month in these genes.
    This picture is one of a routine response by an organism to changes in its environment that, oh, by the way, happen to coincide with the genetic changes that occur with aging.
Rate of Progress in This Field of Gene Chip Studies of Calorie-Restriction/Aging
    Silicon chip densities are doubling every two years. It's interesting to correlate the number of genes monitored on a silicon gene chip with this Moore's-Law rate of improvement. The first gene-chip analysis of which I'm aware was performed by Weindruch and Prolla in 1999. They examined 6,347 genes. The next gene chip analysis, performed by Spindler, et al, in 2001, was able to accommodate more than 11,000 genes. This latest paper, submitted for publication at the end of 2003, tracks 20,000 genes. Following Moore's Law, by this year (2004) or next, gene chips should be available that can accommodate all 30,000 genes in the mouse genome (and could handle all 30,000 genes in the human genome).
    It';s also impressive to see how far this field has advanced in two or four years.
Permanence of Caloric-Restriction Effects
    The question remains: do all the changes that occur during caloric restriction disappear after caloric restriction is terminated?
    I'm guessing they don't. I suspect that if someone lives in a caloric-restricted mode for a few years, and, given high levels of HDL, low levels of LDL, fluffier choesterol particles, and low levels of insulin and blood sugar, ends up with arteries cleaned out, their arteries will retain that state after the subjects discontinue calorie-restriction. Atherosclerotic deposits may build up again, but it would take a while for this to happen. Similarly, in the case of the 18 subjects in the Washington University study, the 40% reduction in the intima thickness of the carotid arteries would take a while to re-thicken (if they ever did). In short, I think that, although levels of biochemicals mediated by the "aging genes" involved with caloric-restriction might change rapidly with variations in the level of caloric restriction, structural improvements might persist after calorie-restriction is discontinued.
Metformin and Other Potential Anti-Aging Drugs
    It's probably appropriate to again mention metformin as a possible drug to partially reverse aging without necessarily engaging in caloric-restriction. 
    There's also the possibility of screening for other drugs that might have anti-aging potential.
    The Spindler/University-of-California-Riverside team is currently repeating a lifespan test conducted by Dr. George Roth at the National Institute on Aging that indicated a 20% increase in the maximum lifespan of mice-on-metformin regime.
The Long-Term Potential for Resetting Age-Modulated Genes
    If this model of gene changes with caloric restriction should happen to be correct, then it wouldn't address aging as well as some intervention that would reset the "ages" intrinsically associated with the various "aging-affected" genes. If these aging genes could durably be restored to more-youthful settings, then this model would predict that a measure of true rejuvenation should occur.

Another Line of Attack
    Another line of attack on this problem hinges upon the fact that fertilized zygotes are refurbished after fertilization takes place. A ferment of DNA repair takes place at this time, and presumably, other kinds of cleanup also occur then. If we can find a way to trigger that refurbishment and rejuvenation without de-differentiating cells, and without their progressing to develop an embryo (all we want is the cleanup), maybe we can harness an effective, existing rejuvenation mechanism to restore our differentiated cells, including our post-mitotic brain and muscle cells.

(To Be Continued)