From immune senescence and insulin resistance to obesity and sarcopenia: iNKT cell as bridge?

In the physiological process of aging, different major players are involved. Sarcopenia, defined as a critical loss of muscle mass and function, an increase of the visceral fat proportion, insulin resistance and immune senescence are all contributing to the disability and mortality in older adults. The interactions between these communicating processes and the molecular mechanisms underlying them are poorly understood but increasing evidence is pointing towards inflammatory cytokines as common link. Adipokines and myokines are important in the pathogenesis of sarcopenia, obesity and insulin resistance, with IFNg, TNFa, IL-6, IL-2, IL-8, MCP-1 and IL-15 as known cytokines taking part herein. Despite this knowledge, the role of immune senescence and of possible key ageing immune cells in this network , is still an unresolved question. We speculate that part of the answer can be found in a relatively recent discovered leukocyte type: the invariant natural killer T-cell (iNKT). iNKT cells are a regulatory type of T-cells with innate-like properties that recognize glycolipids in the context of the non-classical MHC molecule CD1d. Our hypothesis of a pivotal role for iNKT cells in sarcopenia, visceral obesity, insulin resistance and immune senescence is based on the following insights: (i) iNKT cells are very potent and flexible cytokine-producers that secrete large amounts of Th1 and/or Th2 cytokines depending on the physiological context; (ii) iNKT cells quantitatively and qualitatively change with aging, e.g. the peripheral iNKT cell amount decreases with age; (iii) iNKT cells play a crucial role in obesity-induced insulin resistance; (iv) impaired mitochondrial autophagy in sarcopenia is related to dysfunctional immune system; (v) there is a bidirectional crosstalk between sarcopenia and insulin resistance. This proposed link will be explored by investigating how selected endogenous and exogenous glycolipids affect muscle mass and function. As such, our findings will contribute to an improved pathophysiological understanding of sarcopenia with diagnostic and therapeutic clinical applications.

Toegankelijkheid:Open