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Calorie Restriction (CR) Mimetics

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What is a CR Mimetic?

A CR (Calorie Restriction) mimetic may -- if successful -- enable organisms to derive many of the health and life-extending benefits seen in calorie-restricted diets. This may, then, allow the organism to "eat normally" and enjoy a longevous lifespan. The efficacy of such compounds would, upon safe and successful testing in animal subjects, pave the way for substantial increases in human lifespan.

How does a CR Mimetic work?

Ingram believes that targeting glycolysis is the most efficient CR mimetic strategy because it directly affects the production of insulin.(8)

Is there any molecular and/or empirical evidence? And what compounds have currently been identified as potential CR mimetics?

The Major Players (molecules / compounds):

2-DG (2-deoxy-D-glucose) [see, this article; other refs below]. Basically, 2DG does not block nutrient absorption, but throws a wrench in glycolysis, 'starving' the cell for fuel even as you digest all of your food.(9). Threshold Pharmaceuticals claims they are "conducting a Phase 1 trial of daily 2DG as a single agent and in combination with Taxotere to evaluate the safety, pharmacokinetics and maximum tolerated dose in patients with solid tumors. We plan to also conduct a Phase 1 trial of single doses of 2DG to evaluate its effect on prostate metabolism. We are developing 2DG based on its specificity for targeting tumor cells and extensive human safety data, as well as recently demonstrated animal efficacy that we and our collaborators at the University of Miami published in Cancer Research in January 2004."(20)
Iodoacetate (18, 19)
NMN -- Nicotinamide mononucleotide (see Sinclair; also Joe Rogan interview Jan 29, 2019)
Rapamycin (Sirolimus)
Metformin appears to produce a CR mimetic effect, and extended lifespan in mice, as noted by Biomarker Pharmaceuticals.(1)
Resveratrol : found in grapes and red wine. Currently being marketed by several supplement companies.
R(+)-Lipoic Acid (16, 17)

Other Candidates:

N-TERT-BUTYL HYDROXLAMINE (NtBHA) and PBN
Modulators of NPY: The neuropeptide Y
Exanadin: The agent exendin, (exanatide)
PYY3-36
Leptin
Telomere-length restoration (experimental drugs being developed by Geron)

Also:

Intermittent fasting (???)

References

1: Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5524-9. Epub 2004 Mar 25. Related Articles, Links Temporal linkage between the phenotypic and genomic responses to caloric restriction.

Dhahbi JM, Kim HJ, Mote PL, Beaver RJ, Spindler SR.

BioMarker Pharmaceuticals, Incorporated, 900 East Hamilton Avenue, Campbell, CA 95008, USA.

Caloric restriction (CR), the consumption of fewer calories while avoiding malnutrition, decelerates the rate of aging and the development of age-related diseases. CR has been viewed as less effective in older animals and as acting incrementally to slow or prevent age-related changes in gene expression. Here we demonstrate that CR initiated in 19-month-old mice begins within 2 months to increase the mean time to death by 42% and increase mean and maximum lifespans by 4.7 (P = 0.000017) and 6.0 months (P = 0.000056), respectively. The rate of age-associated mortality was decreased 3.1-fold. Between the first and second breakpoints in the CR survival curve (between 21 and 31 months of age), tumors as a cause of death decreased from 80% to 67% (P = 0.012). Genome-wide microarray analysis of hepatic RNA from old control mice switched to CR for 2, 4, and 8 weeks showed a rapid and progressive shift toward the gene expression profile produced by long-term CR. This shift took place in the time frame required to induce the health and longevity effects of CR. Shifting from long-term CR to a control diet, which returns animals to the control rate of aging, reversed 90% of the gene expression effects of long-term CR within 8 weeks. These results suggest a cause-and-effect relationship between the rate of aging and the CR-associated gene expression biomarkers. Therefore, therapeutics mimicking the gene-expression biomarkers of CR may reproduce its physiological effects.

PMID: 15044709 [PubMed - in process]

2: Human Implications of Caloric Restriction's Effects on Aging in Laboratory Animals

3: Scientific American: Aug 2002: The Serious Search for an Anti-Aging Pill

4: Rapid identification of candidate CR mimetics using microarrays

5: Effects of Caloric Restriction on Age-related Disease and Lifespan

6: Calorie Restriction Mimetics By Marios Kyriazis.

7: ALT-711

8: theaustralian.news.com.au

9: Ingram: gen.cam.ac.uk/iabg10/ppts/Ingram.mp3

10: The Anti-Aging Pill, by Bill Sardi

11: The Methuselah Mouse Prize

12: Nutrition.org -- Hansen 131 (3): 900S