FGF21 is one of the targets for potential pharmaceutical intervention to modestly slow aging that has emerged from the past decades of research into calorie restriction. Evidence suggests that there are significant differences between mice and humans in levels of FGF21 in response to aging and calorie restriction, however. A fair amount of this research is focused on obesity as a condition, rather than or in addition to aging, as FGF21 appears to be involved in the mechanisms that determine weight gain in response to diet. The paper noted here suggests that FGF21 has quite different behavior in these two circumstances. This and the general tenor of other research from the past few years combines to make this is a much less attractive area of work for anyone intending to build novel calorie restriction mimetic therapies.
Pharmacological treatment with FGF21 ameliorates age-related metabolic disorders such as insulin resistance, dyslipidemia, and obesity in rodents, and pilot studies in humans indicate that treatment with an FGF21-analog has beneficial effects on hyperlipidemia and body weight. Sustained increases in FGF21 levels attained by transgenic overexpression of FGF21 extend the lifespan of mice, suggesting that FGF21 is a pro-longevity hormone. Circulating FGF21 levels in humans increase with age from 5 to 80 years in healthy individuals independently of body composition. In contradiction, low levels of FGF21 are related to healthy aging in centenarians. In addition, endurance exercise in elderly individuals reduces FGF21 levels.
Thus, it has been suggested that the increases in FGF21 that parallel aging are related to the appearance of an age-related FGF21-resistant state, as has been proposed in metabolic diseases. In obese and diabetic patients, FGF21 levels are abnormally elevated and an FGF21-resistant state has been claimed to accompany these pathologies. In this study, we analyzed FGF21 levels and alterations in the expression of genes encoding components of the FGF21-responsive molecular machinery in adipose tissue from aged individuals so as to ascertain whether altered FGF21 responsiveness that develops with aging jeopardizes human health and/or accelerates metabolic disturbances associated with aging.
We studied a cohort of 28 healthy elderly individuals (≥70 years) with no overt signs of metabolic or other pathologies and compared them with a cohort of 35 young healthy controls (≤40 years). Serum FGF21 levels were significantly increased in elderly individuals compared with young healthy controls. This is in line with previous reports describing an increase in FGF21 levels with aging. Levels of β-Klotho, the coreceptor required for cellular responsiveness to FGF21, were increased in subcutaneous adipose tissue from elderly individuals relative to those from young controls, whereas FGF receptor-1 levels were unaltered.
Adipose explants from aged and young mice respond similarly to FGF21 "ex vivo". Thus, in contrast to what is observed in obesity and diabetes, high levels of FGF21 in healthy aging are not associated with repressed FGF21-responsiveness machinery in adipose tissue. The lack of evidence for impaired FGF21 responsiveness in adipose tissue establishes a distinction between alterations in the FGF21 endocrine system in aging and chronic metabolic pathologies. Either FGF21 resistance per se does not occur during aging or tissues other than subcutaneous fat are the actual source of such resistance.