Adiponectin Levels and Genotype: A Potential Regulator of Lifespan in Humans

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

Introduction

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=118), their offspring (n=228), and unrelated participants aged over 95 (n=78). Adiponectin levels were significantly greater in participants older than 95 years (p<.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<.02), suggesting that inherited factors play a role in determining adiponectin levels. Over-representation of two common variants in the 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 lifespan through the regulation of adiponectin production and/or secretion.

Background

Insulin resistance is an independent risk factor for glucose intolerance and diabetes as well as cardiovascular disease (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. Several cross-sectional studies show that adiponectin increases with age. This finding appears paradoxical 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 lifespan, leading to a selection bias for survival of those with higher adiponectin levels.

Methods

We studied participants at least 95 years old and recruited the offspring of these individuals. We investigated the relationship 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 that protect from a number of common diseases and/or slow the biological processes of aging.

Results

Adiponectin, a serum protein expressed and secreted exclusively by adipose tissue, plays a protective role against insulin resistance and atherosclerosis in humans and protects the heart from ischemia-reperfusion injury in an animal model. Adiponectin exerts its favorable effects on insulin sensitivity in vivo through a decrease in hepatic glucose production. Adiponectin's anti-atherosclerotic effects are mediated in part by its anti-inflammatory activity on endothelial cells. Plasma adiponectin concentrations are reduced in obese individuals. Weight loss has been shown to increase adiponectin levels. Lower adiponectin levels are characteristic of insulin-resistant states such as lipoatrophy and type 2 diabetes (T2D) as well as with coronary artery disease.

Conclusion

Adiponectin is an excellent candidate gene for longevity. The study of its levels in centenarians, their offspring, and unrelated participants aged over 95 suggests that inherited factors play a role in determining adiponectin levels. Over-representation of two common variants in ADIPOQ in male long-lived individuals combined with their independent association with elevated plasma adiponectin levels suggests that their presence may promote increased lifespan through the regulation of adiponectin production and/or secretion.text seems to be mostly free of spelling errors, but there are some issues with grammar and punctuation that need to be addressed. Here is the processed text:

Controls examined unadjusted crude data; and (iii) offspring and controls, where crude data were adjusted for age (except age and sex), sex (except sex), and BMI (except age, sex, BMI, and % fat). Examination was performed as previously described (2, 20, 21). The presence of metabolic syndrome was determined using National Cholesterol Education Program (NCEP), Adult Treatment Panel III (ATP III) criteria (25). Percentage body fat was determined using bioelectric impedance analysis (BIA), performed with a Tanita BIA body fat analyzer (Body Fat Monitor Scale, BF-625; Tanita Corporation of America Inc., Arlington Heights, IL). BIA is used in many epidemiological studies including the age group of the offspring and controls and has been shown to be a better representative of risks associated with increased fat mass compared to BMI. Therefore, it should be helpful. Associations of adiponectin levels with other variables were estimated using regression on an indicator variable for the group, stratifying for age, sex, and BMI. In defining strata for age, cut points of 65, 70, 75, 80, and 85 years were used (Figure 1). Spearman correlations for BMI, % fat, and age were adjusted for age and sex (except age). Spearman correlations for metabolic syndrome-associated traits (i.e., blood pressure, HDL, LDL, triglycerides, glucose, waist circumference and HDL and LDL particle sizes) were adjusted for age, sex and BMI (Table 2).