The practice of calorie restriction, a reduction of up to 40% below the usual ad libitum calorie intake, while still obtaining optimal levels of dietary micronutrients, is well known to slow aging and extend life in near all species and lineages tested to date. Calorie restriction produces sweeping changes in the operation of cellular metabolism, such as upregulation of a range of cellular stress responses, including the maintenance processes of autophagy. It also, however, has the obvious outcome of greatly reducing body fat, particularly the visceral fat that clusters around the organs of the abdomen.

Visceral fat tissue is metabolically active and quite harmful over the long term, so there is always the question of the degree to which the benefits of calorie restriction derive from loss of fat tissue versus upregulated autophagy and the like, and how that balance is different between species. Visceral fat tissue creates chronic inflammation via a variety of mechanisms: cell signaling that is similar to the results of infection; the immune response to debris from dead fat cells; increased numbers of senescent cells in fat tissue. Chronic inflammation then accelerates the development and progression of all common age-related disease. We can see this in the epidemiology of the obese and overweight, as these individuals suffer a shorter life expectancy, a greater risk of age-related disease, and higher lifetime medical costs, with these disadvantages scaling in size with ever greater excess fat tissue.

Yet, on the other hand, if autophagy is disabled through genetic manipulation, calorie restriction no longer functions to extend life span in mice. This data strongly argues for the primacy of upregulated cellular housekeeping over loss of visceral fat tissue as the primary driver of slowed aging via calorie restriction. Yet again, consider that researchers have also shown that surgical removal of visceral fat from mice has a significant effect on life span, though not as great as calorie restriction, which argues an opposite conclusion. It is a challenging phenomenon to investigate.

The open access paper noted here discusses another fat-related aspect of the calorie restriction response, which is to enhance the plasticity of fat deposits, their ability to transform from harmful to beneficial forms of fat tissue. Taken at the high level, white fat is harmful, while brown fat is beneficial – the real picture is somewhat more complex, but this will do as a starting point. As we age the browning of white fat is diminished, but calorie restriction helps to maintain this function, with consequent benefits to health over the long term, distinct from those related to the amount of fat present in the body.

Long-term caloric restriction ameliorates deleterious effects of aging on white and brown adipose tissue plasticity

Aging is associated with an increased risk of metabolic disorders such as obesity, insulin resistance (IR), and other manifestations of metabolic syndrome in both humans and rodents. In parallel with these alterations, a low grade of inflammation has also been described in several tissues associated with aging. Aging is typically associated with increased adiposity and redistribution of adipose tissue (AT), characterized by a loss of subcutaneous adipose depot mass and a gain of fat in the abdominal visceral compartment.

Caloric restriction (CR) is the most efficient intervention to delay the deleterious effects of age-related metabolic diseases. Previous studies in several animal models have shown that CR has physiological effects on lifespan, and reduces body weight and glucose and insulin serum levels. Whether CR interventions in humans slow aging is not yet known. Accumulating data indicate that moderate CR with adequate nutrition has numerous beneficial effects against obesity, diabetes, inflammation, and cardiovascular diseases. However, the mechanisms involved in the amelioration of aging effects by CR are not well understood. Accretion of AT has been related to the development of age-associated metabolic alterations such as IR. Moreover, reduction of adiposity by CR or fat removal have demonstrated to ameliorate age-associated IR. The improvement of the metabolic status achieved by CR may well be due, at least in part, to the decreased adiposity.

Furthermore, increased adiposity by hypertrophy and/or hyperplasia has been demonstrated to increase macrophage infiltration. This circumstance, together with changes in adipocyte physiology that includes hypoxia, reticulum, and oxidative stress, leads to an inflammatory state which is a key factor in the AT expandability capacity. Nevertheless, AT is a complex organ with different localizations and functions beyond its traditional role as a fat storage unit.

A complete understanding of CR effects on AT biology requires the elucidation of whether these effects are preferentially mediated by white AT (WAT) and/or brown AT (BAT), the contribution of specific WAT depots, and the relevance of differentiation/trans-differentiation to beige AT. WAT also has an important endocrine role by secreting different peptide hormones (adipokines) including adiponectin, which regulates insulin sensitivity, as well as glucose and energy homeostasis. In contrast to WAT, BAT plays a central role in energy expenditure via expression of uncoupling protein 1 (UCP-1). BAT is the major site for both cold- and diet-induced thermogenesis, and its atrophy has been observed in obese and older individuals in association with increased visceral fat and hyperglycemia. Consequently, defective WAT and BAT function may exacerbate the development of metabolic complications of obesity/aging.

Here, we aimed to investigate whether the plasticity of the WAT and BAT depots (hypertrophy and/or hyperplasia, extracellular matrix remodeling, inflammation, and browning or whitening capacity) is differentially affected at middle age, and whether moderate CR results in beneficial metabolic effects regulating the functionality of these AT depots. We show that several metabolic alterations of old animals are already being developed in middle-aged animals. These alterations include development of IR, altered WAT and BAT plasticity, as well as alteration of thyroid axis status, which can be mitigated, at least to some extent, by moderate and long-term CR.

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