Age-associated changes in innate and adaptive immunity: role of the gut microbiota

Abstract

Aging is generally regarded as an irreversible process, and its intricate relationship with the immune system has garnered significant attention due to its profound implications for the health and well-being of the aging population. As people age, a multitude of alterations occur within the immune system, affecting both innate and adaptive immunity. In the realm of innate immunity, aging brings about changes in the number and function of various immune cells, including neutrophils, monocytes, and macrophages. Additionally, certain immune pathways, like the cGAS-STING, become activated. These alterations can potentially result in telomere damage, the disruption of cytokine signaling, and impaired recognition of pathogens. The adaptive immune system, too, undergoes a myriad of changes as age advances. These include shifts in the number, frequency, subtype, and function of T cells and B cells. Furthermore, the human gut microbiota undergoes dynamic changes as a part of the aging process. Notably, the interplay between immune changes and gut microbiota highlights the gut's role in modulating immune responses and maintaining immune homeostasis. The gut microbiota of centenarians exhibits characteristics akin to those found in young individuals, setting it apart from the microbiota observed in typical elderly individuals. This review delves into the current understanding of how aging impacts the immune system and suggests potential strategies for reversing aging through interventions in immune factors.

Keywords: adaptive immunity; aging; cGAS-STING; gut microbiota; gut microbiota aging; innate immunity.

Figure 1

Mechanisms of changes in innate immunity during human aging. During the aging process, the innate immune system undergoes changes that impact various immune cells, giving rise to a spectrum of aging-related diseases. Neutrophil counts increase with age and they migrate from the bone marrow to infiltrate peripheral tissues. Additionally, an upregulation of the inflammatory regulator gene Aw112010 results in an elevated number of classical monocytes expressing the gene MHCII in aging mice, potentially triggering atherosclerosis. The aging-related rise in beta-2 microglobulin (β2M) levels is positively correlated with age and may contribute to an increase in circulating Ly6C^Hi monocytes. This elevation could lead to chronic inflammation, adversely affecting cardiac function. Moreover, aging induces the polarization of macrophages from the M1 subtype to the M2 subtype by expanding intermuscular adipose tissue in skeletal muscles. When subjected to complexed immunoglobulin G Toll-like receptor (c-IgG-TLR) stimulation, anti-inflammatory M2 macrophages can paradoxically produce pro-inflammatory cytokines, potentially contributing to conditions like rheumatoid arthritis. In the elderly, the number of CD56^dim NK cells significantly increases, accompanied by heightened expression of the inhibitory receptor CD57, which may underlie age-related immune dysfunction. Furthermore, chronic inflammation in old age, coupled with increased extracellular matrix (ECM) levels, may contribute to elevated mast cell numbers. Concomitant with the rise in mast cell numbers, the expression level of FDF-2 in rats also increases, suggesting mast cells’ potential involvement in age-related tissue remodeling by promoting fibrosis.

Figure 2

cGAS-STING signaling pathway regulates immune system in aging. Mechano-defective extracellular matrix (ECM) triggers the inactivation of nuclear YAP/TAZ, resulting in diminished expression of ACTR2 and LaminB1, along with the loss of the actin cap and nuclear deformity. Subsequent exposure to cytoplasmic DNA and its binding to cGAS facilitate cGAS-STING activation, ultimately causing cellular senescence and the manifestation of aging phenotypes. Moreover, PINK1 deficiency is correlated with mitochondrial dysfunction, which can also activate the cGAS-STING signaling pathway. Treatment with the STING inhibitor H-151 and the cGAS inhibitor RU.521 both demonstrated a reduction in the expression of senescence signaling mediators and SASP, thereby highlighting their potential as therapeutic interventions.

Figure 3

Aging in the regulation of adaptive immunity. Both T cells and B cells are pluripotent stem cells, differentiated from hematopoietic stem cells (HSCs). In the bone marrow, HSCs undergo differentiation, giving rise to progenitor T (pro-T) and pro-B cells. Subsequently, pro-T cells migrate to the thymus, where they undergo somatic recombination to transform into naïve T cells. These naïve T cells then migrate to the lymph nodes. On the other hand, pro-B cells undergo somatic cell recombination and V(D)J recombination, transitioning into immature B cells. These immature B cells migrate to the lymph nodes and spleen to actively participate in the immune response. Adaptive immunity comprises two types: humoral and cell-mediated. B cells mediate humoral immunity, and the reduction in telomere length due to telomerase deficiency during aging hinders B cell production. Additionally, the apoptosis-inducing drug dexamethasone, along with improper feedback from aged age-associated B cells producing TNF-α, inhibits precursor B cell production, ultimately decreasing the overall B cell count. Cell-mediated immunity, on the other hand, is orchestrated by T cells. Age-related telomere shortening results in a significant decline in the expansion ability of T cell clones, leading to a generational reduction in CD4⁺ T cells and, consequently, a decrease in lifespan.

Figure 4

Five stages the gut microbiota goes through during human aging. As individuals age, the composition of the human gut microbiota undergoes distinct phases: an initial phase, a transitional phase, a stable phase, a recession phase, and a rejuvenation phase. In the initial stage, various factors impact the gut microbiota of newborns. Specifically, infants born via cesarean section experience a transition from Firmicutes to Bacteroidetes and Proteobacteria, while those born vaginally have Proteobacteria and Firmicutes as the predominant phyla. During the transitional phase, early weaning has a limited impact on the infant gut microbiota at the phylum level but leads to an enrichment of Veillonellaceae. Notably, Ruminococcaceae and Faecalibacterium show significant increases during the weaning stage. By the age of 3, toddlers experience a substantial increase in both the quantity and variety of their gut microbiota, reaching a level of maturity comparable to that of adults, entering a stable stage. However, distinctions persist between the gut microbiota of children and adults. Blautia in the Lachnospiraceae family is more abundant in the adult cohort, while Bacteroides in the Bacteroidaceae family is more prevalent in the child cohort. As individuals progress into the recession phase of aging, a decrease in the Firmicutes and Bacteroidetes ratio serves as an indicator. Centenarians, in particular, display unique gut microbiota profiles distinct from the average elderly population. Their microbiota undergoes a rejuvenation phase, suggesting that the distinctive microorganisms associated with longevity may play a role in maintaining youth and potentially reversing aging.