Metabolic reprogramming in inflammaging and aging in T cells

Abstract

Aging represents an emerging challenge for public health due to the declined immune responses against pathogens, weakened vaccination efficacy, and disturbed tissue homeostasis. Metabolic alterations in cellular and systemic levels are also known to be cardinal features of aging. Moreover, cellular metabolism has emerged to provide regulations to guide immune cell behavior via modulations on signaling cascades and epigenetic landscape, and the aberrant aging process in immune cells can lead to inflammaging, a chronic and low-grade inflammation that facilitates aging by perturbing homeostasis in tissues and organs. Here, we review how the metabolic program in T cells is influenced by the aging process and how aged T cells modulate inflammaging. In addition, we discuss the potential approaches to reverse or ameliorate aging by rewiring the metabolic programming of immune cells.

Keywords: T cells; immunometabolism; inflammaging.

Figure 1

During the aging process, clonal expansion of HSCs skews toward the generation of myeloid precursors and reduces the output of newly formed lymphoid precursors. Thymic involution, which is the shrinkage in size of the thymus, also contributes to the loss of the T-cell compartment renewal in aged individuals. Aged T cells also display altered chromatin landscape, accumulate DNA damages, and acquire some exhaustion characteristics, including upregulated expression of TOX, PD-1, and Lag3, and senescence markers such as KLRG1 or CD57. They also secrete proinflammatory cytokines like TNF and osteopontin.

Figure 2

mTOR pathway is activated and maintained in aged T cells, leading to high glycolytic metabolic profile. This pathway presents multiple therapeutic opportunities such as targeting AMPK with metformin or mTOR directly with rapamycin. The mitochondrial machinery is also dysfunctional in aged T cells due to impaired mitochondrial biogenesis, accumulation of damages and declined autophagy activity. NAD⁺/NR supplementation can fuel many redox reactions and improve mitochondrial function. Antioxidants like vitamin E or NAC can prevent mitochondrial ROS mediated damages and improve the cellular redox balance. Reduced autophagy activity in aged T cells can be reactivated by spermidine to promote memory T cells.