Aging adipose: Depot location dictates age-associated expansion and dysfunction

Abstract

Adipose tissue has a variety of diverse functions that maintain energy homeostasis. In conditions of excess energy availability, adipose tissue increases its lipid storage and communicates the nutritional abundance to various organs in the body. In conditions of energy depletion, such as fasting, cold exposure, or prolonged exercise, triglycerides stored in adipose tissue are released as free fatty acids to support the shift to catabolic metabolism. These diverse functions of storage, communication, and energy homeostasis are shared between numerous adipose depots including subcutaneous, visceral, brown, beige, intramuscular, marrow, and dermal adipose tissue. As organisms age, the cellular composition of these depots shifts to facilitate increased inflammatory cell infiltration, decreased vasculature, and increased adipocyte quantity and lipid droplet size. The purpose of this review is to give a comprehensive overview of the molecular and cellular changes that occur in various aged adipose depots and discuss their impact on physiology. The molecular signature of aged adipose leads to higher prevalence of metabolic disease in aged populations including type 2 diabetes, cardiovascular disease, Alzheimer's disease, and certain types of cancer.

Keywords: Brown adipose tissue; Osteoporosis; Sarcopenia; Senescence; White adipose tissue.

Figure 1:. Impact of age range on adipose tissue cellular abundance.

A) Time scale for phases of aging including mature adult being 3–6 months in mice (20–30 years in humans), middle-age of 10–14 months in mice (38–47 years in humans), old age of 18–24 months in mice (56–69 years in humans), and very old of 24 months+ in mice (70 and above in humans). Modified from [8]. B) Single cell RNA-sequencing using microfluidic droplet (droplet) of combined adipose tissue from old age and very old age in male and old age in female C57BL6J mice. Data from Tabula Muris Senis [5].

Figure 2:. Changes in Tissue Composition with Aging from Tabula Muris Senis.

A) uniform manifold approximation and projection (UMAP) and B) bar graph from FACS of gonadal white adipose tissue from 3- and 24-month old C57BL6JN mice. Acronyms: mesenchymal stem cell (MSC), Cluster of differentiation 4/8 (CD4/CD8), natural killer (NK).

Figure 3:. Depot Specific Changes in Aging Adipose Tissue.

The various adipose tissue depots in mice have a range of function from thermogenesis, regulation of glucose homeostasis through adipokine production, and lipid storage. These tissues expand and contract in a depot specific manner between the stages of aging from mature adult, middle age, and old age.

Figure 4:. Key Transcriptional Regulators in Brown, White, and Beige Adipose Tissue.

A large body of literature has focused on the characterization of transcriptional regulation in adipocyte differentiation and maintenance. Transcriptional regulators that drive the adipogenic program (black lettering) and inhibitors of adipogenesis (red lettering) have been describes in brown, white, and beige adipocytes. Although there is significant overlap between these depots, unique transcriptional regulators have been identified for white and beige adipocytes. More work is needed to understand how these transcriptional regulators change with aging in a depot specific manner.