Optimal body weight for health and longevity: bridging basic, clinical, and population research

Abstract

Excess body weight and adiposity cause insulin resistance, inflammation, and numerous other alterations in metabolic and hormonal factors that promote atherosclerosis, tumorigenesis, neurodegeneration, and aging. Studies in both animals and humans have demonstrated a beneficial role of dietary restriction and leanness in promoting health and longevity. Epidemiological studies have found strong direct associations between increasing body mass index (BMI) and risks of developing type 2 diabetes, cardiovascular disease, and several types of cancer, beginning from BMI of 20-21 kg m(-2). Although a recent meta-analysis suggests that overweight individuals have significantly lower overall mortality than normal-weight individuals, these data are likely to be an artifact produced by serious methodological problems, especially confounding by smoking, reverse causation due to existing chronic disease, and nonspecific loss of lean mass and function in the frail elderly. From a clinical and public health point of view, maintaining a healthy weight through diet and physical activity should remain the cornerstone in the prevention of chronic diseases and the promotion of healthy aging.

Keywords: body mass index; calorie intake; disease prevention; health; obesity.

Figure 1

Risk of death associated with body mass index among male nonsmokers without chronic health conditions, according to age. The annual risk of death is expressed as both the RR (Panel A) and the absolute amount of additional risk (risk difference) (Panel B) per 100 000 population, as reported in the American Cancer Society Cancer Prevention Study 2. From: Byers T (2006). Overweight and mortality among baby boomers–now we’re getting personal. N Engl J Med 355,758–60.

Figure 2

Relation between body mass index up to 30 and the relative risk of type 2 diabetes, hypertension, coronary heart disease, and cholelithiasis in women (Panel A) and men (Panel B). Relation between the change in weight and the relative risk of type 2 diabetes, hypertension, coronary heart disease, and cholelithiasis in women (Panel C) and men (Panel D). From: Willett WC, Dietz WH, Colditz GA (1999). Guidelines for healthy weight. N Engl J Med. 341, 427–434.

Figure 3

Joint effect of body mass index at age 18 and weight change on healthy survival in the Nurses’ Health Study. Adjusted odds with 95% confidence intervals. Multivariable model adjusted for age (years), education (registered nurse, bachelor, master, or doctoral degree), husband’s education (less than high school, some high school, high school graduate, college graduate, or graduate school), marital status (married, widowed, separated/divorced/never married), postmenopausal hormone use (never used, past user, or current user), smoking status (never smoked, past smoker, current smoker 1–14, 15–24, or ≥25 cigarettes/day), family history of heart disease (yes/no), family history of diabetes (yes/no), family history of cancer (yes/no), vigorous physical activity (hour/week), polyunsaturated–saturated fat ratio (in fifths), intakes of trans fat, alcohol, and cereal fiber (all in fifths), and intakes of fruits and vegetables and red meat (in thirds), all defined at baseline. From Sun Q, Townsend MK, Okereke OI, Franco OH, Hu FB, Grodstein F (2009). Adiposity and weight change in midlife in relation to healthy survival after age 70 in women: prospective cohort study. BMJ. 339, b3796.

Figure 4

Adipose tissue as an endocrine organ. A chronic positive energy balance induces adipose tissue expansion (red circles) and recruitment of M1 stage macrophages. Enlarged adipocytes and activated macrophages secrete proteins and lipids, called adipokines, that promote inflammation (e.g., IL-6, TNF-alpha, MCP-1, MIF, resistin), insulin resistance (reduced adiponectin and omentin; increased TNF-alpha, leptin, RBP4, resistin, and nonesterified free fatty acids), cell proliferation (leptin, IGF-1, TGF-β, adipocyte-derived type VI collagen), and blood pressure and coagulation dysfunction.

Figure 5

Dietary restriction (DR)-induced metabolic, molecular, and cellular adaptations. A chronic negative energy balance induced by dietary restriction triggers multiple metabolic adaptations including a reduction in circulating levels of growth factors (i.e., IGF-1), anabolic hormones (e.g., insulin, testosterone, estradiol, leptin), inflammatory cytokines (e.g., IL-6 and TNF-alpha), and key hormones that regulate thermogenesis and cellular metabolism (e.g., triiodothyronine (T3), cathecolamines), and an increase in hormones that suppress inflammation (e.g., cortisol, ghrelin, and adiponectin). Concomitantly, several key molecular adaptations take place, including a down-regulation of the insulin/IGF pathway (i.e., PI3K/Akt/mTOR), and an upregulation of two energy-sensing pathways (i.e., SIRT and AMPK) which activates FOXO. The activation of FOXO in turn modifies several ‘longevity genes,’ including up-regulation of antioxidant genes (e.g., SOD2), DNA repair genes (e.g., DDB1), autophagy genes (e.g., beclin), and a down-regulation of genes that control cell proliferation (e.g., cyclin D). DR induces also a down-regulation of inflammatory pathways (e.g., NFkB), and an up-regulation of genes that enhance protection against molecular damage (e.g., Nrf2, HSP70). These DR-induced metabolic and molecular modifications are responsible for several important cellular adaptations, that antagonize the accumulation of macromolecular damage, abnormal cell proliferation, and cellular senescence (Martin et al., ; Fontana et al., ,; Fontana et al., ; Guarente, ; Selman & Withers, ; Chen et al., 2010).