Thymic fatness and approaches to enhance thymopoietic fitness in aging

Abstract

With advancing age, the thymus undergoes striking fibrotic and fatty changes that culminate in its transformation into adipose tissue. As the thymus involutes, reduction in thymocytes and thymic epithelial cells precede the emergence of mature lipid-laden adipocytes. Dogma dictates that adipocytes are 'passive' cells that occupy non-epithelial thymic space or 'infiltrate' the non-cellular thymic niches. The provenance and purpose of ectopic thymic adipocytes during aging in an organ that is required for establishment and maintenance of T cell repertoire remains an unsolved puzzle. Nonetheless, tantalizing clues about elaborate reciprocal relationship between thymic fatness and thymopoietic fitness are emerging. Blocking or bypassing the route toward thymic adiposity may complement the approaches to rejuvenate thymopoiesis and immunity in elderly.

Figure 1. Thymic adiposity in humans

The magnetic resonance imaging of thymus in metabolically healthy humans reveals age-related thymic adiposity. The Region of Interest (ROIs) depicting the thymus is highlighted by yellow arrows. The fat in the thymus appears whitish (upper panel) while thymic remnants are visible as pale area within the ROI. Lower panel shows thymic imaging in same subjects at similar locations after fat saturation. Since lipid appears as a high signal on T1 weighted images, the fat saturation sequences were applied to render the signal from fat null at the tracheal bifurcation. Upon application of fat-sat sequence, thymic tissue is visible (lower panel) in 25-year old individuals while in 45-year old subjects the area between sternum and ascending aorta is largely devoid of lymphoid tissue.

Figure 2. Scanning electron microscopy of thymus of 68 year old subject

Thymus from a 68-year-old patient observed by scanning electron microscopy. A large number of fatty cells (F) and reticular epithelial cells (R), with a small number of thymocytes (T), can be observed in elderly subjects. (previously published as figure 5 by Cavalotti et al 2008, Microsc Res Tech. 71: 573–578.)

Figure 3. Thymic Adipocytes

Location of thymic adipocytes in 18mo old thymi of C57/B6 mice. (A) Subcapsular cortical adipocytes, (B) Interseptal adipocytes (C) Trabecular adipocytes, * denotes cortical areas of thymus undergoing adipogenic involution. Dotted line indicates corticomeduallry junction and adjacent ectopic adipocytes which could be in the PVS. Cortex (c) and Medulla (m). (D) Thymus from 18m old mouse maintained on 40% caloric restriction shows absence of adipocytes and maintenance of thymic architecture during aging.

Figure 4. Approaches to reverse immunosenescence

Approaches to reverse immunosenescence. CR and metabolic regulators such as ghrelin, leptin, GH and IGF-1 can partially reverse age-related thymic involution. Increased thymopoiesis by these agents (including LHRH and FGF7/KGF, IL7 and IL-15) increases naïve cells and enhanced T cell repertoire diversity.