An Omics View of the Inflammation of Aging

Aging is characterized by chronic inflammation, disruptive of cell and tissue function, a sizable contribution to the onset and progression of all of the common age-related conditions. The causes of this inflammation are known at the high level, such as the increasing presence of senescent cells and damage-associated molecular patterns, such as DNA debris from dead and dying cells. At the detail level, the real of genomics, transcriptomics, proteomics, and the other omics, much remains to be cataloged. There is the hope that a full map of inflammation in aging would point out more and better regulatory or signal molecules that could be targeted by therapies, but this type of approach has so far proven less effective than hoped, given the side-effects it produces. The goal of blocking only excessive inflammation, without blocking essential inflammation, requires a focus on the causes of inflammation, rather than sabotage of the initiation or progression of inflammation.

The immune system undergoes numerous and profound changes with aging. Hallmarks of immune aging are (a) a state of proinflammatory activation characterized by high circulating levels of proinflammatory cytokines - such as IL-6 and TNF-α - and localized tissue inflammation, and (b) an aberrant response to antigens and pathogens that could either be blunted, such as in flu vaccination, or excessive, such as in response to SARS-CoV-2. Considerable research in both animal models and humans has examined the causes and consequences of inflammaging. Although increased levels of inflammatory mediators (mostly IL-1, IL-6, TNF-α, and its receptors) are detected in all elderly individuals, higher levels of these biomarkers are associated with increased risk for many chronic conditions, including dementia, disability, and physical frailty. Inflammation's causal role in cardiovascular disease was established by the CANTOS trial (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study), which demonstrated that IL-1β inhibition reduced the risk of cardiovascular events versus the placebo, particularly in participants whose IL-6 levels were initially elevated.

Mechanisms identified as hallmarks of aging biology and immune cell dysfunction have all been hypothesized as causes of inflammation. Aging researchers now recognize that measuring a few cytokines in circulation fails to capture the complexity and potential ramifications of inflammaging. Immune cells in tissues, particularly lymphocytes and resident macrophages, show tissue-specific age-related changes likely connected to specific pathological processes. By measuring hundreds or thousands of molecules in a few drops of blood, scientists are attempting to identify (a) signatures of accelerated aging that are both informative of the complexity and diversity of the response and predictive of health outcomes and (b) key molecules and molecular mechanisms that can be targeted for intervention.

Given the extreme complexity of inflammaging, we focus herein on a few topics that have attracted considerable attention and controversy in the field. First, we discuss cellular senescence as a source of local and systemic inflammation. We highlight evidence that mitochondrial dysfunction is a nexus that binds impaired mitophagy with DNA damage and cellular senescence to ultimately foster a chronic inflammatory state. We then summarize efforts to identify circulating signatures of inflammation through "omics." Finally, we review emerging data indicating that inflammation is involved in brain aging and dementia. Our intent is to discuss the causes and consequences of inflammaging and to enrich the research agenda toward the development of new therapeutic strategies.

Link: https://doi.org/10.1172/JCI158448

Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.