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

Xiaohui Ma, Radhika Muzumdar, Ilan Gabriely, Gil Atzmon, Nir Barzilai

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)339-344
Number of pages6
JournalClinical Neuroscience Research
Issue number5-6
StatePublished - 2003
Externally publishedYes

Bibliographical note

Funding Information:
The leptin related studies were supported by grants from the National Institutes of Health (RO1-AG18381, and by the Core Laboratories of the Albert Einstein Diabetes Research and Training Center (DK 20541). The longevity study was supported by grants from the Paul Beeson Physician Faculty Scholar in Aging Award, the Ellison Medical Foundation Senior Scholar Award, RO1 (AG-18728-01A1), the General Clinical Research Center (MO1-RR12248-05), and the Diabetes Research and Training Center (DK 20541) at the Albert Einstein College of Medicine. We are indebted to the centenarians and their families for the dedication and enthusiasm with which they participated in this study. We are also grateful to the following institutions, which assisted in recruiting our participants: The Hebrew home for the aging in Riverdale, NY; Kittay House in the Bronx, NY; The Hebrew home hospital in west Hartford, CT; The Jewish home for the aged in New Haven, CT; All under the aegis of the association for the Jewish aging services in Washington, DC.


  • Centarians
  • Cognitive function
  • HDL cholesterol
  • Leptin
  • Visceral fat

ASJC Scopus subject areas

  • Neuropsychology and Physiological Psychology
  • Neurology
  • Clinical Neurology
  • Psychiatry and Mental health
  • Biological Psychiatry


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