Why Does the Aging Metabolism Bias Towards Fat Accumulation and Lipid Deposition?

Irina Conboy's pithy description of what aging does to the operation of metabolism runs much as follows: "stem cells are sleeping, so damage is not regenerated. Instead you now make fibrous tissue, and deposit fat tissue to replace the damage. Then gradually over time, you just turn into this big scar and big fat blob." It is certainly the case that the older body seems to tend to hold on to lipids, create fat tissue, and put fats and other lipids into cells where they are usually not found in large amounts in youth. We might well ask why this happens. Is it the result of damage, some form of dysregulation of normal metabolism that is entirely harmful, or is it at least in part an evolved compensation that helps to attenuate some of the consequences of the underlying molecular damage that causes aging?

The authors of today's open access paper argue that both adaptive and maladaptive processes are in play. Nothing in biology is simple, and the observed redistribution of fat and changes in metabolism may be both harmful and protective when considered in various contexts, or when pieces of the whole are examined in isolation. That in later years it becomes challenging to maintain a good body weight, as the amount of work required to attain that goal ever increases, is no excuse for letting things slide, of course. While it may well be the case that some aspects of excess fat tissue are protective, the epidemiological evidence overwhelmingly demonstrates that, when taken as a whole, being even modestly overweight raises the risk of age-related disease, increases lifetime medical cost, increases mortality, and reduces life expectancy. Those negative effects scale up as the weight and excess fat tissue increase.

The Dual Role of the Pervasive "Fattish" Tissue Remodeling With Age

With advancing age, lean mass and bone mineral density decrease, while total fat mass increases and changes its distribution, particularly in the abdominal region, often without concomitant changes in body mass index (BMI). In mammals, fat mass accumulates as adipose tissue or ectopic lipid deposition. Adipose tissue is a dynamic organ involved in the regulation of energy homeostasis, mainly divided in three types, brown (BAT), white (WAT), and BEIGE which differ in embryogenesis, anatomy, and function. While BAT possesses high levels of mitochondria and is specialized in fat burning to generate heat, WAT is characterized by a low density of mitochondria and it is generally involved in lipid storage in two biological distinct compartments: subcutaneous (SAT) and visceral (VAT) adipose tissue. WAT is not only involved in the storage of lipids, but also plays an important role as immuno-endocrine organ.

With advancing age, BAT mass declines, while WAT increases reaching the maximum peak by early old age and changing its distribution toward a higher proportion of VAT. WAT redistribution is also accompanied by an accumulation of fat mass in non-adipose tissues and organs, such as muscle, liver, heart, pancreas and others, that normally contain only small amounts of fat, stored within lipid droplets (LDs). Adipose tissue shows also an extraordinary plasticity, in fact it can differentiate into another type of adipose tissue, such as BEIGE or replace the parenchyma of organs that undergo involution with age, such as the thymus.

The maintenance of a balanced amount of fat mass is crucial for health and survival. According to the "thrifty phenotype" theory, humans were selected to accumulate fat depots to face periods of food shortage. However, while a critical lower threshold of fat content exists, an upper threshold is apparently missing, and adipose tissue can accumulate in great amounts. The absence of an upper threshold for fat accumulation is probably due to the fact that this phenomenon did not occur in the wild frequently enough to undergo selection, or, alternatively, resulted neutral for the fitness of individuals.

With aging, the "thrifty phenotype" seems to emerge more dramatically, and the balance is tilted toward an increase of fat mass, at the level of VAT and SAT as well as in ectopic sites (liver, muscles, etc.). This increase in fat deposition at the level of SAT and VAT can be considered an adaptive response to modified health conditions interacting with contingent environmental conditions, leading eventually to decreased energy expenditure. However, in some cases the storage of surplus energy can not be claimed as the reason for fat accumulation, especially when this occurs ectopically at the expenses of other tissue types with important vital functions, as in the case of thymic involution or skeletal muscle infiltration.

In this case, it seems that fat deposition in the form of WAT is a sort of physiological program (genetically determined?) for organs and tissues undergoing age-related atrophy or involution. Different stem cell subpopulations such as muscle fibro-adipogenic progenitors and bone marrow mesenchymal stem cells preferentially differentiate to adipocyte with age, therefore, we are tempted to speculate that the pathway leading to this cell type is a sort of a default choice in involution processes. Should this speculation be verified, the reasons for this choice remain elusive.

The accumulation of WAT has been for long time viewed as detrimental, being the source of pro-inflammatory mediators and other important endocrine modulators and strongly associated with metabolic diseases such as insulin resistance and type II diabetes, cardiovascular diseases, and cancer. However, it is not totally clear whether this negative role is present also in extreme old age. Actually, data on body composition in nonagenarians and centenarians are largely missing, even though the BMI of these people is usually lower than that of younger (70-80 years-old) persons. It is possible that, as for other risk factors like lipid serum profile and inflammatory parameters, also the presence of a consistent amount of WAT can be important for survival at very advanced age. Further studies are needed to verify this hypothesis.

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