Categories: agingtargeting

Targeting aging cells improves survival

Older age is associated with increased COVID-19 severity and mortality (1). Whether this is due to preexisting age-related health conditions or aging per se is currently unclear. On page 295 of this issue, Camell et al. (2) show that cell senescence, a hallmark of biological aging (3), contributes to mortality in old mice upon infection with mouse hepatitis virus (MHV), a mouse β-coronavirus that is similar to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Mirroring findings from human COVID-19, they show that old—but not young—mice infected with MHV succumb rapidly to viral infection. They demonstrate that treatments to remove senescent cells (senolytics) significantly improve survival in older mice, even when initiated 3 days after infection. These findings provide a biological explanation for the effect of age on COVID-19 severity and strongly support the testing of drugs that target senescence in older patients with SARS-CoV-2 infection.

Cellular senescence amplifies damaging inflammation

Senescent cells secrete inflammatory mediators and proteases, which contribute to age-related disease. Upon coronavirus infection, senescent cell load and the secretome increase, which drives inflammation, tissue damage, further infection, inflammation-related pathology, and death. Removal of senescent cells with senolytic drugs reduces inflammation to below the “young” threshold, allowing disease resolution and survival.

GRAPHIC: V. ALTOUNIAN/SCIENCE

” data-hide-link-title=”0″ data-icon-position=”” href=”https://science.sciencemag.org/content/sci/373/6552/281/F1.large.jpg?width=800&height=600&carousel=1″ rel=”gallery-fragment-images-1910663503″ title=”Cellular senescence amplifies damaging inflammation Senescent cells secrete inflammatory mediators and proteases, which contribute to age-related disease. Upon coronavirus infection, senescent cell load and the secretome increase, which drives inflammation, tissue damage, further infection, inflammation-related pathology, and death. Removal of senescent cells with senolytic drugs reduces inflammation to below the “young” threshold, allowing disease resolution and survival.”>

Cellular senescence amplifies damaging inflammation

Senescent cells secrete inflammatory mediators and proteases, which contribute to age-related disease. Upon coronavirus infection, senescent cell load and the secretome increase, which drives inflammation, tissue damage, further infection, inflammation-related pathology, and death. Removal of senescent cells with senolytic drugs reduces inflammation to below the “young” threshold, allowing disease resolution and survival.

GRAPHIC: V. ALTOUNIAN/SCIENCE

Senescence is a tumor-suppressive, nonproliferative state induced by chronic cellular stress or damage, and senescent cells accumulate with increasing age. Cell senescence has been suggested to be a major biological driver of age-related dysfunction and morbidity as well as further exacerbating disease states such as diabetes and atherosclerosis (4). These pro-aging effects are due in large part to a complex secretome that contains inflammatory cytokines and chemokines, angiogenic growth factors, and tissue-remodeling metalloproteases, collectively known as the senescence-associated secretory phenotype (SASP) (5). Although beneficial under acute stress or injury, the persistent SASP that occurs as a result of senescent cell accumulation in older adults leads to chronic inflammation (6). This “inflammaging” may be pathogenic for multiple age-related diseases. Transplantation of senescent cells into young mice induces a broad range of age-related diseases (7), whereas their removal from old mice improves health across multiple organ systems and increases life span (8).

Why might senescent cells be detrimental in infectious diseases such as COVID-19? Camell et al. show that in vitro exposure of senescent human cells to pathogen-associated lipopolysaccharide (LPS) and the S1 subunit of the SARS-CoV-2 spike protein (which mediates cell entry) leads to increased expression of senescence markers and the SASP. Similarly, MHV-infected old (but not young) mice exhibit increased cell senescence and SASP factors, suggesting that pathogen exposure can amplify detrimental inflammation because of senescent cells (see the figure). These findings extend our understanding of the role of viral infection in driving formation of SASP-producing senescent cells (9). Notably, SASP factors—especially interleukin-1α (IL-1α)—were found to reduce the expression of interferon-induced transmembrane proteins (IFITMs), a first-line of antiviral defense, as well as increase the expression of the SARS-CoV-2 entry receptor angiotensin-converting enzyme 2 (ACE2) and co-receptor transmembrane protease serine 2 (TMPRSS2) in nonsenescent cells. Hence, SASP secretion predisposes adjacent cells to higher viral infection and poorer innate antiviral responses, in addition to increasing inflammation and tissue damage.

It can be deduced from these findings that the higher the senescent cell burden, the more likely SARS-CoV-2 infection is to lead to severe COVID-19. Older adults (>70 years) and those with chronic conditions such as obesity and diabetes, who alr

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