Insulin Metabolism May Affect Life Span via Effects on Innate Immune Function

Insulin metabolism is one of the better studied areas of biochemistry in connection with aging, and one of the earliest areas of focus for the aging research community. Dysfunction of insulin metabolism, meaning loss of insulin sensitivity, is characteristic of obesity and the slide into type 2 diabetes, and the manifestations of diabetes in some ways resemble accelerated aging. While one should not consider high levels of a single form of dysfunction to be accelerated aging, since normal aging is a specific mix of various forms of damage and dysfunction, it can be worth bearing in mind that there are mechanistic overlaps between diseases and aging.

In today's open access paper, researchers connect insulin sensitivity with better function of the innate immune cells known as macrophages. Better insulin sensitivity ensures that macrophages change their behavior to be more ready to clear molecular waste and damaged cells from tissues, while suppressing inflammatory signaling. The researchers suggest that this could be enough to explain the link between insulin metabolism and life expectancy. Since insulin metabolism touches on near every other aspect of cellular behavior, that is a challenging hypothesis to prove, but it is something to think on. The function and inflammatory state of the immune system is clearly important in aging.

Enhanced insulin-regulated phagocytic activities support extreme health span and longevity in multiple populations

The immune system plays a central role in many processes of age-related non-communicable diseases such as cardiovascular diseases, type 2 diabetes, and dementia. Activated immune functions, which frequently describe as inflammation, has been recognized as part of their pathophysiologies. However, accumulating evidence challenges this assumption and suggests that the immune system may instead get mounting adaptive responses to chronic stressors, prolonging the chances of survival of an organism. To address this argument, one possible way is to investigate the immune signatures in long-lived individuals (LLIs; mean age of greater than 95 years old) and centenarians, the "aging champions" who achieved successful human aging and exhibited medical histories with remarkably low incidences of common age-related disorders. Since inflammaging and immunosenescence is a common feature of chronological aging in ordinary people contributing to enhances risks of mortality at advanced age; this proposes that a better functioning immune system, with stronger pro-survival and stress handling abilities, are likely at play in shaping extreme longevity.

The immune system can be schematically seen as two divisions. The ancestral/innate arm is mainly represented by monocytes, natural killer (NK) and dendritic cells (DC); whereas the adaptive arm is represented by the B lymphocytes and T lymphocytes. As if a functioning immune system requires a homeostatic balance between the two, gene expression profiles of circulating immune cells would likely reveal important clues that are crucial for achieving healthy aging. A recent single-cell transcriptomic study reported that expansion of cytotoxic CD4 T cells is a unique immune signature among supercentenarians; whereas previous bulk transcriptome studies proposed that shift in lymphocyte to myeloid cell ratio, enhanced autophagy-lysosomal function; reduction in ribosomal biosynthesis, or upregulated apoptotic Bcl-xL is however crucial to successful aging. It remains unclear if any common immune features unique to extreme longevity exist among LLIs regardless to their origins; and whether the associated molecular signatures can provide insights for practical translations.

By harnessing the wealth of single-cell and bulk transcriptome datasets available in the public repositories; we uncovered that significant induction of innate immune monocytes with enhanced lysosomal and phagocytic activity is a previously unrecognized, common, and unique immune signature among LLIs from various geographical origins and ethnicities. The life cycle of these monocytes in LLIs is enhanced and primed to a M2-like macrophage phenotype. Monocytes are the major immune cells that express insulin receptor (INSR). Functional characterization revealed an insulin-signaling centric immunometabolism network which supports multiple aspects of phagocytosis. Such reprogramming is associated to a skewed trend of DNA demethylation, particularly at the promoter regions of multiple phagocytic genes, so as a direct transcriptional effect induced by the nuclear INSR. Together, these findings highlighted that preservation of insulin sensitivity hence an active innate monocyte-driven phagocytic activity is a defense mechanism in safeguarding healthy lifespan and extended longevity.

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