Adiponectin Levels and Genotype: A Potential Regulator of Life Span in Humans

1 2 1 2 3 Gil Atzmon, Toni I. Pollin, Jill Crandall, Keith Tanner, Clyde B. Schechter, 4 5 1 1 Philipp E. Scherer, Marielisa Rincon, Glenn Siegel, Micol Katz, 6 2,7 1 Richard B. Lipton, Alan R. Shuldiner, and Nir Barzilai

1Institute for Aging Research, Diabetes Research and Training Center Department of Medicine, Albert Einstein College of Medicine, New York.

Departments of 3Family and Social Medicine, 4Cell Biology, 5Pediatrics, and 6Neurology, Albert Einstein College of Medicine, New 7Geriatrics Research and Education Clinical Center, Veterans Administration Medical Center, Baltimore.

Although caloric restriction in numerous models extends life, longevity in humans is suggested to be limited by the increased prevalence of obesity. Adiponectin, a fat-derived peptide, has a protective role against age-related disease, and thus is an excellent candidate gene for longevity. We studied adiponectin levels in centenarians (n ¼ 118), their offspring (n ¼ 228), and unrelated participants ,95 (n ¼ 78). Adiponectin levels were significantly greater in participants older than 95 years (p ¼ .01), an effect that was independent of sex and body mass index (BMI). Adiponectin levels in the offspring were higher (following adjustment for age, sex, and BMI) compared to controls (p ¼ .02), suggesting that inherited factors play a role in determining adiponectin levels. Over-representation of two common variants in Adiponectin gene (ADIPOQ) in male long-lived individuals combined with their independent association with elevated plasma adiponectin levels (in men and women) suggests that their presence may promote increased life span through the regulation of adiponectin production and/or secretion.

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states such as lipoatrophy (5) and type 2 diabetes (T2D) (12), as well as with coronary artery disease (5). Further support for the close relationship between insulin sensitivity and adiponectin comes from clinical studies in which treatment with the insulin-sensitizing thiazolidinediones increases adiponectin levels (13–15).

diabetes, cardiovascular disease (CVD), Alzheimer’s disease, and cancer. However, exceptionally long-lived humans, that is, those older than 95 years, have survived to more than double their life expectancy at birth, and have often been spared these age-related diseases (1). Indeed, offspring of centenarians have 50% lower prevalence rates of these diseases than do the control groups, suggesting that they may inherit protection against these major causes of mortality (2). Insulin resistance is an independent risk factor for glucose intolerance and diabetes as well as CVD. Thus, one of the mechanisms underlying protection from these age-related diseases in exceptionally long-lived individuals and their offspring is that those who survive to extreme old age have preserved their insulin sensitivity (3).

Several cross-sectional studies show that adiponectin increases with age (16–19). This finding appears paradox- ical because normal aging is associated with insulin resistance and increased risk of CVD and suggests that aging may be associated with some degree of adiponectin resistance or possibly that increased adiponectin levels extend life span, leading to a selection bias for survival of those with higher adiponectin levels. To elucidate whether exceptionally long-lived individuals are protected from the development of aging-associated disease as a result of increased adiponectin levels, we studied participants at least 95 years old. We also recruited the offspring of these individuals, reasoning that many of these individuals will also be enriched with phenotype(s) and genotype(s) that enable exceptional longevity, relative to controls of similar ages who do not have a family history of exceptional longevity. In these individuals, we investigated the relation- ship between adiponectin levels, ADIPOQ genotypes, relevant metabolic phenotypes, and longevity. Identification of genes and biological markers that are conducive to exceptional longevity may provide insights into mechanisms

Adiponectin, a serum protein expressed and secreted exclusively by adipose tissue, plays a protective role against insulin resistance (4) and atherosclerosis (5–8) in humans, and protects the heart from ischemia-reperfusion injury in an animal model (9). Adiponectin exerts its favorable effects on insulin sensitivity in vivo through a decrease in hepatic glucose production (4). Adiponectin’s anti-atherosclerotic effects are mediated in part by its anti-inflammatory activity on endothelial cells (5,7,8). Plasma adiponectin concen- trations are reduced in obese individuals (10). Weight loss has been shown to increase adiponectin levels (11). Lower adiponectin levels are characteristic of insulin-resistant

that protect from a number of common diseases and/or slow the biological processes of aging (20).

for this group. However, it has not been validated in the centenarians, and because the test depends on distribution of water, it may misrepresent the exact percentage of fat and lean body mass. Low-density lipoprotein cholesterol (LDL) levels, high-density lipoprotein cholesterol (HDL) levels, and average particle sizes were determined by nuclear magnetic resonance (NMR) spectroscopy at LipoScience, Inc. (Raleigh, NC) as previously described (26,27). Large lipoprotein particle sizes were defined as .8.9 nm for HDL and .21.3 nm for LDL. Serum adiponectin levels were measured using a human adiponectin enzyme-linked immunosorbent assay (ELISA) kit (ALPCO Diagnostics, Windham, NH).

Participants and Phenotyping