Rejuvenation Update - Part I

April 7, 2004

Tonight's Calorie Restriction Presentation on CBS' Evening News
Tonight, on the CBS Evening News with Dan Rather, there was some footage on calorie restriction at the end of the broadcast "Fewer Calories, Longer Life?"
Partial Rejuvenation
A few weeks ago, I joined the Calorie Restriction Society. I've learned a lot from being on the CR e-mail lists. One subject that has become clearer is that of the partial rejuvenation that caloric restriction provides. I didn't figure this out for myself, but I can't quote from the e-mail of the very-smart individual who did because what appears on e-mail lists is privileged information.
An Interpretation of Dr. Spindler's Latest Study
In Dr. Spindler's latest study, his mice ate their fill, and aged normally until they were 19 months old... the human equivalent of "60 to 65". Then they were put on a diet that restricted their calories 44%. In human terms, this would be equivalent to dropping from 2,600 calories a day to about 1,450 calories a day.. Finally, he followed them until they died. What Dr. Spindler found in his latest "Proceedings of the National Academy of Sciences" paper was that the remaining  lifespan of the average caloric-restricted mouse increased from 11.8 months to 16.8 months, give or take a bit. In other words, caloric restriction increased the lifespan of the average mouse by 5.0 months. So the average lifespan of his mice (presumably in his control group) was 19 months + 11.8 months = 30.8 months. If we divide the 5 months of additional lifespan that caloric restriction bestows upon the average mouse by the 11.8 months of the average mouse' additional lifespan, we arrive at a lifespan increase for the average mouse of 42%, which is what has been quoted in the press relases reporting on this study.
A second (and in my opinion, very important) fact that Dr. Spindler discovered is that after his caloric-restricted mice had been caloric-restricted for 2 months (and were 21 months old), their mortality rate had dropped by a factor of 3.1.
Shifting to Human Calenders
Now I'm going to try to convert this into human equivalents because my next number involves human mortalities. Also, in the end we're going to want to know what this might possibly do for us, rather than what it does for mice.
The articles about Dr. Spindler's results, quote the "60 to 65" equivalence for 19-month-old mice. That leads to some mighty long-lived mice, but these mice were already "state-of-the-art" in terms of natural longevity.
If I equate 60 human years to 19-month-old mice, I get a mouse-to-human conversion factor of 60/19 = 3.15 human years/"mouse month".
If I equate 65 human years to 19-month-old mice, I get a mouse-to-human conversion factor of 65/19 = 3.42 human years/"mouse month".
But the important thing is the approximate value of this conversion factor, although it would be good to have a more accurate number.
The 2-month mortality reduction period in mice translates into 6.3 to 6.84 years to reduce mortality by a factor of 3.1 for humans starting caloric restriction at 60-to-65.
In other words, a human being starting caloric restriction at 60 would be 66.3 years old before caloric restriction fully reduced his mortality by a factor of 3.1 A 65-year-old would be 71.84 years old before caloric restriction fully reduced her mortality by 3.1.
Although it would take 6-to-7 years to fully effect the 3.1:1 reduction in mortality, I suspect that the lion's share of this mortality reduction may occur within six months.
Converting a 3.1 Reduction in Mortality Rates to a Reduction in Effective Biological Age
Now in humans, the mortality rate doubles every 8 years. This is probably not exactly true, and it may break down in old age, when the doubling time may change, but I'll use this number for the purposes of this calculation since I'm trying to arrive at a concept more than a precise number. (Of course, these studies are probably still preliminary, and there's nothing that says that their results have to be directly transferable from mice to humans, but we have to start somewhere. My guess is that they may agree somewhat closely.)
Now if mortality doubles in humans every 8 years, and caloric restriction reduced the mortality rate by a factor of 2, we could say that, from the standpoint of mortality, we've subtracted 8 years from the biological age of a 66.3 to 71.84-year-old human.
If caloric restriction reduced the mortality rate by a factor of 4, we would have effectively subtracted 16 years from the "actuarial age" of a human.
In practice, it reduced the mortality rate (in mice) by a factor of 3.1. So how many years does that represent in human terms?
We could write:
3.1 = 2^(t/8).
Then if we take the decimal logarithm of both sides, we have log(3.1) = t/8 * log(2). But
log(3.1) = 0.49136
log(2)    = 0.30103, so that
0.49136 = 0.30103 * t/8, or
t = 8 * 0.49136/0.30103 = 8 * 1.6323 = 13.058 years = ~ 13 years
So from a mortality point of view, the CR diet should back up humans aged 66.3-71.84 time frame by 13 years.

Now mortality rates are an acid test of location along an aging (survival) curve.

The 13-year figure-of-merit derived above would be the number of years of rejuvenation that elders might be expected to reap if they started caloric restriction at the beginning of old age.
Converting the Remaining Lifespan of Average Mice into Human Terms.
Another, more-direct way to arrive at the overall effect of late-in-life caloric restriction is to multiply the extension of the average lifespan... 5 months... by the conversion factors 3.15 to 3.42. Presumably, this number is greater than the rejuvenation effect because the caloric-restricted humans would be aging slower going forward as a consequence of their caloric restriction.
This gives a total lifespan extension of 15.75 to 17.2 years. This would put the average caloric-restricted lifespan among humans entering caloric restriction at the theshold of old age at, perhaps, 100.

The Lifespan of the Longest-Lived 10%
For the mean lifespan of the longest-lived decile of Dr. Spindler's mice, caloric restriction extended their lifespans from 37.6 months to 43.6 months, or about 6 additional months. In human terms, that would correspond to 18.9 to 20.5 years. If I take the mean of the longest-lived decile in humans to be 88 (I'm making a wild guess), then CRON started at the beginning of old age would take these survivors to 107 to 108.5 years. (I'm certainly finagling here. 37.6 months multiplied by 3.15 translates into the awesome age for the mean of the longest-lived human decile of 118, and 37.6 months times 3.42 leads us to 129 years! These numbers are much too high for the mean of the longest-lived human decile even if, like the mice, they were placed on an optimal diet! And a CRON diet, started at 60 to 65, would be expected, for the longest-lived decile among humans to 137 and 149 years, respectively.)

So it seems to be true: going on a caloric-restricted program late in life can subtract more than a decade from your biological age! What a windfall! Of course, this is all counting chickens, but it's nice to have something to dream on.
Sounds great. It has my vote. Bring on the cake and cookies--oops! How about hot chocolate with green tea in it?

I think the Life Extension Foundation can take great pride in having sponsored Dr. Spindler, and having sponsored a watershed discovery that should do wonderful things for the world.

Part II                                                                   Part III

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