The Geroscience hypothesis postulates that the biological factors of aging, including cellular senescence, are at the origin of several disorders and chronic diseases.13 Senescent cell (SnC) load is low in young, healthy individuals, but increases with aging in many tissues. SnCs also appear at the pathogenic sites of many diseases, including the lungs in COPD, asthma, smoking, and idiopathic pulmonary fibrosis; fatty and other tissues in obesity / diabetes; heart and vessels in cardiovascular disease; brain in Alzheimer’s disease; around cancers; bone in osteoporosis; bone and synovium in osteoarthritis; kidney in kidney disease; and the liver in cirrhosis and steatosis.
Cellular senescence is cell fate, such as differentiation, proliferation, apoptosis, or necrosis. SnCs are in essentially irreversible replicative arrest, while remaining viable and metabolically active. External and internal signals, including genotoxic, metabolic and mechanical / shear stresses can lead to senescence through cascades of transcription factors (eg, p16ENCRE4A/ retinoblastoma protein and / or p53 / p21CIP1). This causes significant changes in gene expression and organelle function (eg, mitochondria, lysosomes), profound morphological and metabolic changes, and resistance to apoptosis. SnCs often develop a secretory phenotype associated with senescence (SASP). This can include pro-inflammatory; pro-apoptotic cytokines (TNF-Î±, IL-1Î±, IL-6, etc.); chemokines which attract, activate and anchor immune cells (IP-10, MCP, etc.); tissue destructive proteases (eg, MMP-3, 9 or 12); prothrombotic factors (PAI-1, etc.); factors that impair stem / progenitor cell function and cause fibrosis (eg, activin-A, TGF-Î²-bound proteins); and ferritin. In addition to proteins and peptides, SASP can include bioactive lipids (eg, fibrosis, systemic inflammation, immune dysfunction, and the spread of senescence (Figure 1).14, 15
The health impact of SnCs has led to the research and discovery of senolytics, drugs that selectively remove SnCs. Short-acting senolytics are effective even when administered intermittently, once every few days or weeks in a âhit-and-runâ approach, potentially reducing side effects. Brief disruption of survival pathways is sufficient to kill SnCs in human cell cultures, in vivo in mice, and in human tissue explants containing SnC. After drug-induced depletion, SnCs take more than a week to re-accumulate if the inducers remain present, at least in vitro. Monthly senolytic administration is as effective as daily doses in relieving certain age-related diseases, for example osteoporosis in mice. These points, along with the satisfaction of a modified set of Koch’s postulates, indicate that senolytics alleviate dysfunction by clearing SnCs, and not by other off-target mechanisms that require continued occupation of a receptor or l engagement of an enzyme. Senolytics relieve multiple conditions in mice, including pulmonary fibrosis, heart failure, vascular dysfunction, dementia, diabetes and its complications; fragility, damage / dysfunction of kidneys, liver and intestines; osteoporosis; osteoarthritis; delay cancer; and extend the lifespan and median lifespan.
Rationale for using geroscientific interventions to treat COVID-19 infection and its sequelae
SARS-CoV-2 can cause hyperinflammation, cytokine storm, acute respiratory distress syndrome (ARDS), myocarditis, generalized thrombosis, persistent symptoms and morbidity (long-haul syndrome) and multiple organ failure , especially in the elderly or chronically ill. Morbidity and mortality from SARS-CoV-2 is strongly associated with age and is also increased in younger people with chronic diseases, including obesity, diabetes, chronic lung disease, smoking, asthma, atherosclerosis, hypertension and immunological, hepatic and renal diseases.16 Consistent with the Geroscience hypothesis, the elderly and patients with diseases associated with senescence are more susceptible to adverse reactions in response to infections (eg, SARS-CoV-2) and frequently develop a more exaggerated inflammatory state than young patients without pre-existing senescence – associated chronic diseases. This has usually been attributed to a dysfunction of the immune system or chronic inflammation. Our âenhancer / rheostatâ hypothesis is that pathogen-associated molecular configuring factors (PAMPs), such as viral antigens, cause a change in SASP from pre-existing SnCs to a more inflammatory, pro-apoptotic and profibrotic SASP,17 potentially exacerbating systemic inflammatory responses and also amplifying the spread of senescence to other cells. The resulting additional SnCs can exacerbate and prolong inflammation, attenuate or delay recovery, lead to persistent frailty, cause long-term tissue fibrosis, and contribute to long-haul syndrome, multiple organ failure and death. .
Agents that target fundamental mechanisms of aging, such as senolytics, have the potential to improve resilience and prevent, delay or reduce morbidity and mortality from infections such as SARS-CoV-2.14, 15, 18, 19 Senolytic fisetin (3,3 â², 4 â², 7-tetrahydroxyflavone, a flavonoid found in many fruits and vegetables and available as a dietary supplement) alleviates multiple disorders associated with senescence in mice, physical dysfunction in mice. elderly mouse and age-related disorders. tissue dysfunction and pathology.20 Studies in a mouse model indicate that Fisetin improves the antibody response and improves clinical outcomes (including mortality) in aged mice that are exposed to infected viruses containing a murine -coronavirus, just like another senolytic regimen, Dasatinib plus Quercetin (D + Q).17 Although ongoing clinical trials of these agents (Table S1) have revealed few or no serious side effects directly related to senolytic drugs, it is still unclear whether senolytics will be safe and effective for older people with SARS. CoV-2 and they should not be used outside of a carefully supervised clinical trial. Given the high morbidity and mortality resulting from SARS-CoV-2 in the elderly and chronically ill patients, a randomized, placebo-controlled, double-blind trial of Fisetin for SNF residents who have a positive rtPCR test for SARS-CoV-2 seems important.