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  • Letter to anti-aging researcher

    May 5, 2014: by Bill Sardi

    Colin Selman
    Institute of Biodiversity
    College of Medicine
    University of Glasgow UK

    From: Bill Sardi, Knowledge of Health, Inc. and Resveratrol Partners LLC, USA

    Having read your recent published paper on the pursuit of effective calorie restriction mimics published in Proceedings of The Nutrition Society (volume 73, page 260-70, 2014; abstract below) and ten years of observing the field of anti-aging research, I can say that the reality of what is going on in the profession is far from what your paper depicts.

    I’m sorry if it sounds like I’m lecturing you here, but I have a theory of aging I want to share.

    Whatever does prolong human life and produce super-longevity works at three different speeds.  Using the accumulation of lipofuscin (cellular debris) as a marker of aging, there is generally little or no lipofuscin observed in living cells under a microscope during the growing years of life.  When growth ceases, lipofuscin begins to accumulate, believed to emanate from the decline in lysosomal enzymes within cells induced by progressive buildup of iron, copper and calcium.

    There is a high demand for minerals during the growth years; iron for red blood cells, copper for connective tissue and calcium for bone.  However, these minerals begin to accumulate once childhood growth ceases.  Mineral accumulation first occurs in males, females dumping iron with their monthly menstrual flow and donating calcium to their offspring.  Full-grown males accumulate 1 excess milligram of iron per day of life and by age 40 have four times as much calcium and twice as much iron stored in their body as an equally-aged female, and exhibit double the rate of diabetes, cancer and heart disease.  Should a woman undergo early hysterectomy she will develop the same rate of disease as males.

    Therefore, lipofuscin progressively accumulates with advancing age and generates free radicals and gene mutations.  The rate of aging increases throughout this time.

    Late in life the rate of aging is known to decrease and this is associated with iron storage (ferritin) leveling off.

    Thus a theory could be developed that overmineralization is what drives aging, not calorie restriction per se.  Eating less food delivers less minerals.

    An experiment conducted at McGill University a few years ago conclusively showed it is minerals and not calories that produce the unusual longevity associated with calorie restriction.  Dietary restriction did not reduce the number of aging deposits in the brain of rodents fed a normal diet but did reduce aging deposits in the brain when a standard calorie-restricted diet with low metallic mineral content was compared against a diet where animals ate a restricted-calorie diet with added metallic minerals.  (Source: Biogerontology 5: 81–88, 2004. Effects of dietary restriction and metal supplementation on the accumulation of iron-laden glial inclusions in the aging rat hippocampus. O. Borten, A. Liberman, B. Tuchweber, S. Chevalier, G. Ferland & H.M. Schipper)

    There is considerable evidence for the Overmineralization theory of aging, both from epidemiology (countries with water and grasslands have cattle, produce iron-rich beef and calcium-rich dairy and have double the rate of heart disease and cancer); and from experience with blood-letting to reduce iron stores which appears to eradicate virtually every age-related disease (

    I won’t go any further in explaining this theory of aging.  The main point is that aging research cannot produce fertile results unless it grasps the proper hypothesis to test.  That may explain all of the extraneous results with calorie restriction.  The Overmineralization theory provides you with the underlying mechanism of CR your paper begs for.

    Epigenetically the closest thing there is to a molecular calorie restriction mimic is a nutraceutical I formulated called Longevinex.  Noted researchers conducted a 12-week global gene array study with rodents and reported that CR significantly differentiated 198 genes (831 if CR diet were adhered to over a lifetime), resveratrol 225 genes, Longevinex resveratrol-based matrix 1711 genes (82% of those 831 genes were switched in the same direction as CR).

    Of course, this study is ignored by researchers and cited by very few and even the researchers who conducted the study won’t lecture on it.  (Source: Short-term consumption of a resveratrol-containing nutraceutical mixture mimics gene expression of long-term caloric restriction in mouse heart. Barger JL, Kayo T, Pugh TD, Prolla TA, Weindruch R. Experimental Gerontology. 2008 Sep; 43(9):859-66.)

    In regard to rapamycin, yes it does produce significant side effects in humans which would eliminate it from practical use, but its main proponent suggests very low doses, maybe 1-3 milligrams, which would make it a hormetic agent that provokes Nrf2, which appears to be a powerful mechanism your paper didn’t explore.  (Source: Selective anti-cancer agents as anti-aging drugs. Blagosklonny MV. Cancer Biology Therapy. 2013 Dec 1; 14(12):1092-1097)

    The research on resveratrol is mixed primarily because researchers over-dose animals and humans, which produces a pro-oxidant effect.  Resveratrol is described as a hormetic agent and as such should be given in modest (but higher than dietary) doses.  Also, aging researchers continue to harp that resveratrol is not bioavailable when its liver metabolites have been found to exert biological action equal to that of free unbound resveratrol.  (Source: How researchers muddy resveratrol science.

    In regard to your comment near the end of your paper that “the vast majority of us” may opt for a calorie restriction mimic.  I can tell you, after a decade of marketing such a pill, the public fears living longer (run out of retirement money, loss of independence) and desires to look younger, not live longer.  A CR mimetic would be a hard sell.

    Your comment that the research community needs to learn how CR mimetics work is almost laughable.  Your profession has had a decade to work on this since David Sinclair obtained considerable publicity for resveratrol pills and you still don’t know?  Clive McCay started all this many decades ago.  Still no proven life-prolonging strategy has been blessed by science.

    As far as the field “moving apace,” it is progressing with the speed of a snail, and it appears to be intentional.

    The resveratrol-based nutraceutical I formulated has been demonstrated to restore vision to hopeless patients with retinal disease, abolish the first sign of blood vessel disease among metabolic patients, and turns mortal heart attacks in the animal lab into non-mortal events.  (Sources: Observation of human retinal remodeling in octogenarians with a resveratrol based nutritional supplement. Richer S, Stiles W, Ulanski L, Carroll D, Podella C. Nutrients. 2013 Jun 4; 5(6):1989-2005; Modified resveratrol Longevinex improves endothelial function in adults with metabolic syndrome receiving standard treatment. Fujitaka K, Otani H, Jo F, Jo H, Nomura E, Iwasaki M, Nishikawa M, Iwasaka T, Das DK. Nutrition Research. 2011 Nov; 1(11):842-7; Restoration of altered microRNA expression in the ischemic heart with resveratrol. Mukhopadhyay P, Mukherjee S, Ahsan K, Bagchi A, Pacher P, Das DK. PLoS One. 2010 Dec 23; 5(12):e15705.)

    The result of all this achievement?  The public doesn’t buy it, doctors don’t embrace it and the aging research community ignores it.  That is the reality your paper misses.

    Bill Sardi


    Proceedings of the Nutrition Society

    Proceedings of the Nutrition Society / Volume 73 / Issue 02 / May 2014, pp 260-270

    Conference on ‘Nutrition and healthy ageing’

    Symposium 3: Nutritional modulation of the ageing trajectory

    Dietary restriction and the pursuit of effective mimetics

    The Nutrition Society Annual Summer meeting, Newcastle University. 15–18 July 2013.

    Colin Selman 

    Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Graham Kerr Building, Glasgow G12 8QQ, UK


    Dietary restriction (DR) has been shown to extend both median and maximum lifespan in a range of animals, although recent findings suggest that these effects are not universally enjoyed across all animals. In particular, the lifespan effect following DR in mice is highly strain-specific and there is little current evidence that DR induces a positive effect on all-cause mortality in non-human primates. However, the positive effects of DR on health appear to be highly conserved across the vast majority of species, including human subjects. Despite these effects on health, it is highly unlikely that DR will become a realistic or popular life choice for most human subjects given the level of restraint required. Consequently significant research is focusing on identifying compounds that will bestow the benefits of DR without the obligation to adhere to stringent reductions in daily food intake. Several such compounds, including rapamycin, metformin and resveratrol, have been identified as potential DR mimetics. Although these compounds show significant promise, there is a need to properly understand the mechanisms through which these drugs act. This review will discuss the importance in understanding the role that genetic background and heterogeneity play in mediating the lifespan and healthspan effects of DR. It will also provide an overview of the most promising current DR mimetics and their effects on healthy lifespan.

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