Does the brain lead the metabolic decline in aging? Lessons from animal models and human centenarians

We hypothesize that age-related metabolic alterations originate in the brain (studies in rodents), and that the functional decline of the brain may be protected by a favorable metabolic profile (studies in human centenarians). The metabolic decline with aging is associated with a progressive increase in fat mass in mammals and caloric restriction enhances life span in rodents. Here we show that a diminished biological response to leptin is a feature of aging. Leptin is a fat derived peptide that decreases body weight, fat mass, improves insulin sensitivity and energy expenditure through its receptors in the hypothalamus. We examined the effects of exogenous leptin on several metabolic parameters as a function of aging in rats. A prolonged elevation in plasma leptin levels in aging rats failed to decrease food intake, total fat mass, and intra-abdominal fat. Furthermore, the effects of leptin on liver triglyceride content, on insulin action and insulin secretion were markedly decreased in these animals compared to young controls. Leptin's failure in this aging model suggests its role in age-associated body fat accumulation, fat distribution and insulin resistance. We propose that a central nervous system resistance to leptin is probably a primary event that leads to the metabolic syndrome of aging, especially when availability of calories is unrestricted. Families of centenarians often have extremely high levels of high-density lipoprotein (HDL), which may have neurological as well as cardiovascular protective effects during aging. Because HDL level declines with aging, we tested if centenarians with higher HDL levels have greater cognitive protection. HDL levels correlated significantly with mini-mental state score (MMSE) of the centenarian, and each decrease in HDL tertile was associated with significant decrease in MMSE. These data suggests that the appearance of cognitive dysfunction in centenarians is associated with a decline in HDL cholesterol. This underscores the protective effects of increased HDL cholesterol, and its role in longevity. Taken together, these data suggest a determinant role for brain in the metabolic decline of aging, and highlight the advantage of favorable metabolic profile on the protection of brain from age-related cognitive decline.