Aging and the hypothalamus: Research perspectives

There are several hypothalamic theories of aging, none of which has been validated. An approach to validation is to search for consequences of anatomic ablations of hypothalamic regions that are functional hallmarks of aging, or consequences of ablation that postpone the appearance of hallmarks of aging or extend longevity. Ablation of the hypothalamic ventromedial nucleus (VMN) in the weanling rat is associated with subsequent increased body fat, glucose intolerance, hyperlipidemia, and decreased renal function. Each of these consequences is characteristic of aging in humans and in several animal models of aging. Ablation of the hypothalamic dorsomedial nucleus (DMN) in the weanling rat leads to a symmetrically smaller animal with normal glucose and lipid metabolism, decreased body fat for size, and reduced risk of decreased renal function and circulating IGF-I levels. These are findings consistent with calorie restriction models in rodents that significantly extend life span. This review compares outcomes of lesions in the VMN, DMN, and lateral hypothalamic area (LHA) for relevance to aging. To establish a relationship between these anatomic areas of the hypothalamus and aging, it is concluded that the VMN, DMN, and LHA lesions should be examined for impact on longevity and compared with data obtained from simultaneously studied intact ad-lib-fed and 40% calorie-restricted animals. Lesioned animals also should be rigorously studied for neurotransmitters (e.g., neuropeptide Y, beta-endorphin, serotonin, corticotropin-releasing factor, and galanin), and for behavioral changes consistent with aging, for accumulation of specific tissue lipofuscin and amyloid that are associated with normal aging and for other age-dependent findings, such as incidence of tumors and cataract.