Leptin and aging: Review and questions with particular emphasis on its role in the central regulation of energy balance

• Leptin-induced anorexia and hypermetabolism show disparate changes during aging.
• Age-related decline primarily affects the hypermetabolic leptin actions.
• Old rats are more sensitive to obesity-induced leptin resistance.
• Calorie-restriction enhances responsiveness to leptin, especially in old rats.
• In absence of obesity, in lean rats, aging increases leptin sensitivity.

Leptin is produced mainly in the white adipose tissue and emerged as one of the key catabolic regulators of food intake and energy expenditure. During the course of aging characteristic alterations in body weight and body composition in humans and mammals, i.e. middle-aged obesity and aging anorexia and cachexia, suggest age-related regulatory changes in energy balance in the background. Aging has been associated with increased fat mass, central and peripheral leptin resistance as indicated by its failure to reduce food intake, to increase metabolic rate and thereby to induce weight loss. Leptin resistance is a common feature of aging and obesity (even in the young). The question arises whether aging or fat accumulation plays the primary role in the development of this resistance. The review focuses mainly on mechanisms and development of central leptin resistance. Age-related decline primarily affects the hypermetabolic component of central catabolic leptin actions, while the anorexigenic component is even growing stronger in the late phase of aging. Obesity enhances resistance to leptin at any age, particularly in old rats, calorie-restriction, on the other hand, increases responsiveness to leptin, especially in the oldest age-group. Thus, without obesity, leptin sensitivity appears not to decrease but to increase by old age. Interactions with other substances (e.g. insulin, cholecystokinin, endogenous cannabinoids) and life-style factors (e.g. exercise) in these age-related changes need to be investigated.