All:
John Schloendorn: Background (without literature backup -- please correct me where I'm wrong): Caloric restriction (CR) at adult onset extends healthy life span in most animal models tested.
Importantly, the only real example of which I can think of a failure was the housefly. It workds pretty darned consistently in vertebrates and, in particular, mammals. The results in cattle are rather crude, however, and we're still waiting for maximum lifespan results in nonhuman primates.
John Schloendorn: In some of these species, a consistent pattern of gene expression changes that occurs relatively soon after CR onset is well documented. (For a list of those changes see e.g. the intro of Berner et al 2004). Is it time to investigate corresponding changes in tissue samples from live human CR volunteers? If yes, has any of it been done? If yes, what was found?
It has not been done
yet. The NIA's
multi-site CALERIE study, the substudy (1) out of Washington University School of Medicine of members of long-term CR folk drawn from the
CR Society, and the Society's own
CR Society Cohort Study are all for the moment just doing the obvious, relatively noninvasive stuff: lipids, glycemia, cardiac stress tests, bracial artery responsiveness, etc. However, CALERIE is going to eventually do muscle and adipose biopsies for gene expression studies:
CALERIE Study Grant Cover:
Hypothesis D. Chronic CR is associated with adaptations in the expression of genes involved in aging, including those related to oxidative stress, energy metabolism (carbohydrate, lipid and protein), and longevity.
Aim D: Measure for differences in the expression of candidate genes in skeletal muscle and adipose tissue.
But you ask, "Is it time to investigate corresponding changes in tissue samples from live human CR volunteers?" and I'm not sure that the answer should be any more than a lukewarm "Sure." Such a study would primarily be of interest to see if the effects of CR at the gene expression profile level would parallel those observed in CR rodents, adding to the case that CR will indeed retard aging in humans. This data would be useful for one of two purposes: to get people to practice CR, or to further the development of CR mimetics (Spindler's company,
Biomarker Pharmaceuticals, is pursuing this.
Now, on the former: I don't know that gene expression studies would add all THAT much incentive to individual humans taking up CR beyond what's already out there (eg, (1-11)) to show that CR in normal-weight persons reduces disease risk and appears to be effective as an anti-aging intervention. The connection between reduced heat shock protein expression or differential regulation of TCA cycle enzymes and an actual health outcome is rather murkier than the effects on risk factors and I suspect major hormones to the average person (although LEF's nonsensical claims about "
Reversing Aging Rapidly With Short-Term Calorie Restriction" (along with the
related editorials and news stories), and the equally misleading followup on a later study, "
BioMarker Pharmaceuticals Develops Anti-Aging Therapy", may have the beneficial side-effect of making their readership take such data more seriously, although for the wrong reasons).
On the other hand, they might well lead to the facilitation of the development of CR mimetics -- but as I've argued elsewhere (12-14), that's a distraction from the real work of developing
more effective, real anti-aging medicine via SENS -- and potentially a widely fatal one, as (a) the tiny pool of resources devoted to developing anti-aging interventions are, at present, almost entirely going that way, and could instead be going to SENS, and (b) for regulatory and scientific reasons, it will likely take much longer (by decades) to develop and document the efficacy of CR mimetics than age-
reversing technologies.
-Michael
1. Fontana L, Meyer TE, Klein S, Holloszy JO.
Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans.Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6659-63. Epub 2004 Apr 19.
PMID: 15096581 [PubMed - indexed for MEDLINE]
2. Walford RL, Mock D, Verdery R, MacCallum T. Calorie restriction in
Biosphere 2: alterations in physiologic, hematologic, hormonal, and
biochemical parameters in humans restricted for a 2-year period. J
Gerontol A Biol Sci Med Sci. 2002 Jun;57(6):B211-24.
3. Velthuis-te Wierik EJ, van den Berg H, Schaafsma G, Hendriks HF,
Brouwer A. Energy restriction, a useful intervention to retard human
ageing? Results of a feasibility study. Eur J Clin Nutr. 1994
Feb;48(2):138-48.
4. Vallejo EA. La dieta de hambre a dias alternos in la alimentacion de
los viejos. [A fasting diet on alternate days in the feeding of the
elderly]. Rev Clin Esp. 1957 Oct 15;63(1):25–7. Spanish.
5. Kagawa Y. Impact of Westernization on the nutrition of Japanese:
changes in physique, cancer, longevity and centenarians. Prev Med. 1978
Jun;7(2):205-17.
6. Suzuki M, Wilcox BJ, Wilcox CD. Implications from and for food
cultures for cardiovascular disease: longevity. Asia Pac J Clin Nutr.
2001;10(2):165-71.
7. Willcox BJ, Willcox DC, Suzuki M. The Okinawa Program: How the
World's Longest-Lived People Achieve Everlasting Health – and How You
Can Too. 2001; New York: Crown Publishers.
7a. Willcox BJ, Willcox DC, Suzuki M. The Okinawa Diet Plan: Get Leaner,
Live Longer, and Never Feel Hungry. 2004; New York: Clarkson Potter,
23-4 and citations.
8. Todoriki H, Willcox DC, Willcox BJ. The effects of post-war dietary
change on longevity and health in Okinawa. Okinawan J Am Stud.
2004;1:55-64. And personal communication, BJ Willcox.
9. Akisaka M, Asato L, Chan YC, Suzuki M, Uezato T, Yamamoto S. Energy
and nutrient intakes of Okinawan centenarians. J Nutr Sci Vitaminol
(Tokyo). 1996 Jun;42(3):241-8.
10. Hursting SD, Lavigne JA, Berrigan D, Perkins SN, Barrett JC.
Calorie restriction, aging, and cancer prevention: mechanisms of action
and applicability to humans. Annu Rev Med. 2003;54:131-52. Includes good
review of results of cancer studies in European famine cohorts.
11. Heilbronn LK, Ravussin E. Calorie restriction and aging: review of
the literature and implications for studies in humans. Am J Clin Nutr.
2003 Sep;78(3):361-9.
12. Rae M.
It's never too late: calorie restriction is effective in older mammals.Rejuvenation Res. 2004 Spring;7(1):3-8. Review. No abstract available.
PMID: 15256039 [PubMed - indexed for MEDLINE]
13. Rae MJ.
Anti-Aging Medicine: Fallacies, Realities, and Imperatives.
J Gerontol A Biol Sci Med Sci. 2005; in press.
14. Rae MJ.
You Don’t Need a Weatherman: Famines, Evolution, and Intervention into Aging.
Gerontology. Submitted.
