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Role of senescence in the chronic health consequences of COVID-19

Open AccessPublished:October 22, 2021DOI:https://doi.org/10.1016/j.trsl.2021.10.003
      While the full impact of COVID-19 is not yet clear, early studies have indicated that upwards of 10% of patients experience COVID-19 symptoms longer than 3 weeks, known as Long-Hauler's Syndrome or PACS (postacute sequelae of SARS-CoV-2 infection). There is little known about risk factors or predictors of susceptibility for Long-Hauler's Syndrome, but older adults are at greater risk for severe outcomes and mortality from COVID-19. The pillars of aging (including cellular senescence, telomere dysfunction, impaired proteostasis, mitochondrial dysfunction, deregulated nutrient sensing, genomic instability, progenitor cell exhaustion, altered intercellular communication, and epigenetic alterations) that contribute to age-related dysfunction and chronic diseases (the “Geroscience Hypothesis”) may interfere with defenses against viral infection and consequences of these infections. Heightening of the low-grade inflammation that is associated with aging may generate an exaggerated response to an acute COVID-19 infection. Innate immune system dysfunction that leads to decreased senescent cell removal and/or increased senescent cell formation could contribute to accumulation of senescent cells with both aging and viral infections. These processes may contribute to increased risk for long-term COVID-19 sequelae in older or chronically ill patients. Hence, senolytics and other geroscience interventions that may prolong healthspan and alleviate chronic diseases and multimorbidity linked to fundamental aging processes might be an option for delaying, preventing, or alleviating Long-Hauler's Syndrome.

      Abbreviations:

      AMPK (AMP-activated protein kinase), COVID-19 (coronavirus disease 2019), COVID-FIS (A phase 2 placebo-controlled pilot study in COVID-19 of Fisetin to Alleviate Dysfunction and Excessive Inflammatory Response in Older Adults in Nursing Homes), CR (caloric restriction), FGA (Facility for Geroscience Analysis), ICU (intensive care unit), IF (intermittent fasting), LTCF (long-term care facility), MCC (multiple chronic conditions), MERS-CoV (Middle East Respiratory Syndrome Coronavirus), mTOR (mammalian target of rapamycin), NAD+ (nicotinamide adenine dinucleotide), NMN (nicotinamide mononucleotide), NR (nicotinamide riboside), PACS (postacute sequalae of SARS-CoV-2 infection), PAMPs (pathogen-associated molecular profile factors), ROS (reactive oxygen species), SARS (severe acute respiratory syndrome), SARS-CoV-1 (severe acute respiratory syndrome coronavirus 1), SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), SASP (senescence-associated secretory phenotype), SNF (skilled nursing facility), TGN (translational geroscience network), WHO (World Health Organization)

      INTRODUCTION

       Incidence/prevalence of Long-Hauler Syndrome

      Initial reports from the World Health Organization (WHO)-China in February, 2020 indicated that clinical recovery from time of onset of COVID-19 symptoms is between 2-6 weeks, the latter being in more severe cases.
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      Globally, patients have expressed frustration with ongoing symptoms, lack of therapeutic solutions, and being directed to treatment for chronic fatigue syndrome and other nonspecific diagnoses. Little is known about why certain people are more susceptible to persistent symptoms after the acute case. However, innate immune system dysfunction and/or cellular senescence and accumulation of senescent cells, which contribute to age-related dysfunction and other chronic diseases, may provide insight into the increased risk of long-term sequelae in older patients. As the reported numbers of elderly or young chronically-diseased patients with Long- Haulers grow, more research is necessary about Long-Hauler Syndrome, its underlying mechanisms, the long-term impact of the virus, and potential interventions.

       Working definitions of the syndrome

      There have been many names given to symptoms lingering after the initial acute case of COVID-19, and there is overlap in this terminology. The UK National Institute for Health and Care Excellence (NICE) created the following clinical definitions of COVID-19 symptoms to help define cohorts of people experiencing prolonged symptoms: 1) acute COVID-19 is the initial onset of symptoms, with symptoms lasting up to 4 weeks; 2) ongoing symptomatic COVID-19 or Post-Acute COVID-19 includes symptoms lasting between 4 and 12 weeks; and 3) Post-COVID-19, Chronic COVID-19, Post-COVID Syndrome, or Long-Haulers Syndrome define symptoms lasting greater than 12 weeks not due to another condition.
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      COVID-19 IN THE ELDERLY AND PEOPLE WITH CHRONIC DISEASE

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       Disease burden and unique aspects of COVID-19 in older adults

      As of September 2021, the β-coronavirus-19 (SARS-CoV-2) pandemic had led to 219 million confirmed cases and 4.5 million deaths worldwide. In the U.S., 81% of deaths were in individuals older than 65 years.
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      Distinct clinical trajectories include survivors with few symptoms, symptomatic survivors, mortality following a prolonged clinical course, and mortality following a rapid clinical course, with each group having somewhat different patterns of initial signs/symptoms.
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      Those with higher symptom burden at the time of an initial positive test have poorer outcomes, though even older adults who are asymptomatic initially have greater mortality risk than those who test negative for COVID-19.
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       Predisposition to Long-Haulers chronic health consequences

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      Older adults with severe initial illness in intensive care units (ICU) can experience long-lasting symptoms, which is not unique to patients with COVID-19, called Post Intensive Care Syndrome (PICS). However, there is another group of patients with mild to moderate symptoms who did not need a lengthy hospitalization or intensive care stay, who present with similar features. Although a small uncontrolled study suggested that Long-Haulers patients can be young without having many pre-existing comorbidities, reports of older adults with Long-Haulers exist and comparative studies are needed to determine the impact of age on the incidence of the syndrome.
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      MECHANISMS

       Geroscience hypothesis

      The Geroscience Hypothesis proposes that targeting aging mechanisms, rather than targeting a single disease, can increase healthspan.
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       Pillars of aging

      The “pillars of aging” include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, dysregulated nutrient sensing, mitochondrial dysfunction, progenitor cell exhaustion, altered intercellular communication, and cellular senescence.
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      Each pillar can contribute to age-related disease and dysfunction, many are known to contribute to chronic diseases, and these aging mechanisms appear to be highly interrelated and even inter-dependent. Each pillar of aging may play a role in interfering with defenses against infection, including innate and adaptive immune responses,
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      The rate of attrition is dependent on a person's comorbidities, including age and disease.
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      Viruses and telomeres competitively utilize similar mechanisms for genomic maintenance.
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      Decreased autophagy is linked to impaired regenerative function in progenitor cells.
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      Viruses, including SARS-CoV-2, also impact progenitor cells, leading to detrimental long-term effects and increasing susceptibility to other age-related conditions.
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      Therapeutics for Long-COVID and more severe acute cases of COVID-19 need to be specifically studied in immunocompromised patients.

       Cellular senescence and COVID-19

      Hayflick and Moorehead first observed cellular senescence, an essentially irreversible cell fate, in human fibroblasts in 1961.
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      Senolytics prevent mt-DNA-induced inflammation and promote the survival of aged organs following transplantation.
      These SASP factors can induce local and systemic inflammation, fibrosis, tissue damage, progenitor cell dysfunction, depletion of nicotinamide adenine dinucleotide (NAD+) and increased production of reactive oxygen species (ROS) by nearby nonsenescent cells, induction of senescence in nonsenescent cells locally and systemically, blood clotting, impaired innate immune responses, and immune system dysfunction.
      • Lewis-McDougall FC
      • Ruchaya PJ
      • Domenjo-Vila E
      • et al.
      Aged-senescent cells contribute to impaired heart regeneration.
      ,
      • Xu M
      • Pirtskhalava T
      • Farr JN
      • et al.
      Senolytics improve physical function and increase lifespan in old age.
      • Chini C
      • Hogan KA
      • Warner GM
      • et al.
      The NADase CD38 is induced by factors secreted from senescent cells providing a potential link between senescence and age-related cellular NAD(+) decline.
      • Prata L
      • Ovsyannikova IG
      • Tchkonia T
      • Kirkland JL.
      Senescent cell clearance by the immune system: emerging therapeutic opportunities.
      • Chini CCS
      • Peclat TR
      • Warner GM
      • et al.
      CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD(+) and NMN levels.
      Thus, accumulation and sustained presence of senescent cells with a SASP can cause dysfunction and contribute to cognitive, metabolic, physical, and vascular dysfunction, tissue fibrosis, disease susceptibility and severity, and mortality.
      • Khosla S
      • Farr JN
      • Tchkonia T
      • Kirkland JL.
      The role of cellular senescence in ageing and endocrine disease.
      ,
      • Xu M
      • Palmer AK
      • Ding H
      • et al.
      Targeting senescent cells enhances adipogenesis and metabolic function in old age.
      ,
      • Xu M
      • Pirtskhalava T
      • Farr JN
      • et al.
      Senolytics improve physical function and increase lifespan in old age.
      ,
      • Xu M
      • Tchkonia T
      • Ding H
      • et al.
      JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age.
      • Roos CM
      • Zhang B
      • Palmer AK
      • et al.
      Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice.
      • Xu M
      • Bradley EW
      • Weivoda MM
      • et al.
      Transplanted senescent cells induce an osteoarthritis-like condition in mice.
      • Schafer MJ
      • White TA
      • Iijima K
      • et al.
      Cellular senescence mediates fibrotic pulmonary disease.
      • Ogrodnik M
      • Miwa S
      • Tchkonia T
      • et al.
      Cellular senescence drives age-dependent hepatic steatosis.
      • Justice JN
      • Gregory H
      • Tchkonia T
      • et al.
      Cellular senescence biomarker p16INK4a+ cell burden in thigh adipose is associated with poor physical function in older women.
      • Tchkonia T
      • Kirkland JL.
      Aging, cell senescence, and chronic disease: emerging therapeutic strategies.
      • Wang B
      • Liu Z
      • Chen VP
      • et al.
      Transplanting cells from old but not young donors causes physical dysfunction in older recipients.
      • Wissler Gerdes EO
      • Zhu Y
      • Weigand BM
      • et al.
      Cellular senescence in aging and age-related diseases: Implications for neurodegenerative diseases.
      • Ogrodnik M
      • Evans SA
      • Fielder E
      • et al.
      Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice.
      There can be benefits from cellular senescence, including facilitating removal of damaged tissues, protection against cancer, aiding in inflammatory responses, fetal development, and in the placenta to promote parturition.
      • Kirkland JL
      • Tchkonia T.
      Senolytic drugs: from discovery to translation.
      ,
      • Demaria M
      • Ohtani N
      • Youssef SA
      • et al.
      An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA.
      • Campisi J.
      Aging, cellular senescence, and cancer.
      • Meuter A
      • Rogmann LM
      • Winterhoff BJ
      • Tchkonia T
      • Kirkland JL
      • Morbeck DE.
      Markers of cellular senescence are elevated in murine blastocysts cultured in vitro: molecular consequences of culture in atmospheric oxygen.
      Hence, interfering with the generation of senescent cells can lead to cancer, impair wound healing, and other consequences.
      • Kirkland JL
      • Tchkonia T.
      Cellular senescence: a translational perspective.
      ,
      • Demaria M
      • Ohtani N
      • Youssef SA
      • et al.
      An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA.
      ,
      • Guida JL
      • Agurs-Collins T
      • Ahles TA
      • et al.
      Strategies to prevent or remediate cancer and treatment-related aging.
      However, timely removal of those already formed senescent cells with a tissue-destructive SASP can alleviate dysfunction related to multiple diseases and aging in preclinical animal models, including delaying or reducing growth of cancers.
      • Kirkland JL
      • Tchkonia T.
      Cellular senescence: a translational perspective.
      ,
      • Wyld L
      • Bellantuono I
      • Tchkonia T
      • et al.
      Senescence and cancer: a review of clinical implications of senescence and senotherapies.
      ,
      • Guida JL
      • Agurs-Collins T
      • Ahles TA
      • et al.
      Strategies to prevent or remediate cancer and treatment-related aging.
      Our ‘Threshold Theory of Senescent Cell Burden’ holds that once senescent cells accumulate and spread to a threshold that is higher than that which the immune system can clear, further senescent cell accumulation and accelerated age- or disease-related dysfunction can ensue.
      • Wissler Gerdes EO
      • Zhu Y
      • Tchkonia T
      • Kirkland JL.
      Discovery, development, and future application of senolytics: theories and predictions.
      ,
      • Kirkland JL
      • Tchkonia T.
      Senolytic drugs: from discovery to translation.
      ,
      • Palmer AK
      • Tchkonia T
      • Kirkland JL.
      Senolytics: potential for alleviating diabetes and its complications.
      Accumulation of senescent cells appears to confer risk for developing a more severe case or complications from COVID-19.
      • Verdoorn BP
      • Evans TK
      • Hanson GJ
      • et al.
      Fisetin for COVID-19 in skilled nursing facilities: senolytic trials in the COVID era.
      ,
      • Camell CD
      • Yousefzadeh MJ
      • Zhu Y
      • et al.
      Senolytics reduce coronavirus-related mortality in old mice.
      ,
      • Nehme J
      • Borghesan M
      • Mackedenski S
      • Bird TG
      • Demaria M.
      Cellular senescence as a potential mediator of COVID-19 severity in the elderly.
      The SASP can impair immune system function.
      • Prata L
      • Ovsyannikova IG
      • Tchkonia T
      • Kirkland JL.
      Senescent cell clearance by the immune system: emerging therapeutic opportunities.
      Aging of the immune system, or immunosenescence, involves an increase in baseline levels of cytokines, including IL-6, IL-RA, TNF-α, and IL-1, which are also SASP factors.
      • Pietrobon AJ
      • Teixeira FME
      • Sato MN.
      I mmunosenescence and inflammaging: risk factors of severe COVID-19 in older people.
      There are increases in pro-inflammatory cytokines in patients with COVID-19, and these levels are related to the severity of cases and clinical outcome.
      • Huang C
      • Wang Y
      • Li X
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      • Sasson JM
      • Campo JJ
      • Carpenter RM
      • et al.
      Diverse humoral immune responses in younger and older adult COVID-19 patients.
      • Zheng HY
      • Zhang M
      • Yang CX
      • et al.
      Elevated exhaustion levels and reduced functional diversity of T cells in peripheral blood may predict severe progression in COVID-19 patients.
      • Liu J
      • Li S
      • Liu J
      • et al.
      Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients.
      • Kroemer A
      • Khan K
      • Plassmeyer M
      • et al.
      Inflammasome activation and pyroptosis in lymphopenic liver patients with COVID-19.
      An excessive inflammatory response to COVID-19 can lead to the worsening of infection and symptoms and, eventually, cytokine storm.
      • Channappanavar R
      • Perlman S.
      Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology.
      It has been reported that complement-mediated microvascular injury is associated with the primary pathophysiology of both COVID-19 progression and long-COVID.
      • Magro C
      • Mulvey JJ
      • Berlin D
      • et al.
      Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases.
      ,
      • Fogarty H
      • Townsend L
      • Morrin H
      • et al.
      Persistent endotheliopathy in the pathogenesis of long COVID syndrome.
      As complement activity differs with age and sex, these factors should be considered in future therapeutic and treatment studies.
      • Gaya da Costa M
      • Poppelaars F
      • van Kooten C
      • et al.
      Age and sex-associated changes of complement activity and complement levels in a healthy Caucasian population.
      Additionally, sustained complement activation may induce or accelerate senescent cell accumulation, which can lead to endothelial dysfunction, possibly contributing to long-COVID pathology.
      • Fogarty H
      • Townsend L
      • Morrin H
      • et al.
      Persistent endotheliopathy in the pathogenesis of long COVID syndrome.
      ,
      • Ganova P
      • Gyurkovska V
      • Belenska-Todorova L
      • Ivanovska N.
      Functional complement activity is decisive for the development of chronic synovitis, osteophyte formation and processes of cell senescence in zymosan-induced arthritis.

       Amplifier/Rheostat hypothesis

      Our team developed an ‘Amplifier/Rheostat Hypothesis’: that the pathogen-associated molecular profile factors (PAMPs) that are expressed by infectious agents can cause the SASP of pre-existing senescent cells to become even more inflammatory and destructive.
      • Wissler Gerdes EO
      • Zhu Y
      • Tchkonia T
      • Kirkland JL.
      Discovery, development, and future application of senolytics: theories and predictions.
      ,
      • Camell CD
      • Yousefzadeh MJ
      • Zhu Y
      • et al.
      Senolytics reduce coronavirus-related mortality in old mice.
      According to this Amplifier/Rheostat Hypothesis, the already increased inflammatory state of aged or chronically ill individuals who have increased pre-existing senescent cell burden, might become more pronounced with SARS-CoV-2 infection.
      • Ogrodnik M
      • Miwa S
      • Tchkonia T
      • et al.
      Cellular senescence drives age-dependent hepatic steatosis.
      ,
      • Pietrobon AJ
      • Teixeira FME
      • Sato MN.
      I mmunosenescence and inflammaging: risk factors of severe COVID-19 in older people.
      This hypothesis might explain why the elderly and patients with pre-existing, cellular senescence-associated conditions are more susceptible to either more severe cases of acute COVID-19 and/or prolonged effects after the initial acute infection, especially if new senescent cells are formed that exceed the senescent cell threshold.
      • Camell CD
      • Yousefzadeh MJ
      • Zhu Y
      • et al.
      Senolytics reduce coronavirus-related mortality in old mice.
      Furthermore, coronaviruses, including SARS-CoV-2 virus, can cause previously nonsenescent cells to become senescent, in part through Toll-like receptor-3, and senescent cell abundance is higher in patients who die from COVID-19 from other causes.
      • Ogrodnik M
      • Miwa S
      • Tchkonia T
      • et al.
      Cellular senescence drives age-dependent hepatic steatosis.
      ,
      • Tripathi U
      • Nchioua R
      • Prata L
      • et al.
      SARS-CoV-2 causes senescence in human cells and exacerbates the senescence-associated secretory phenotype through TLR-3.
      ,
      • Lee S
      • Yu Y
      • Trimpert J
      • et al.
      Virus-induced senescence is driver and therapeutic target in COVID-19.

       Unitary theory of fundamental aging processes

      Though distinct in some respects, the hallmarks of aging may not be fully independent processes. Rather, it appears they are interconnected, with all playing a role in contributing to age-related diseases and disorders. The Unitary Theory of Fundamental Aging Processes posits that targeting one hallmark, or pillar, of aging may influence some or all of the others,
      • Tchkonia T
      • Palmer AK
      • Kirkland JL.
      New horizons: novel approaches to enhance Healthspan through targeting cellular senescence and related aging mechanisms.
      ,
      • Kirkland JL
      • Tchkonia T.
      Senolytic drugs: from discovery to translation.
      Therefore, intervention against one fundamental aging mechanism could impact many of the others. This suggests that intervening by targeting a single fundamental aging mechanism may lead to broad benefits because of an impact on others, potentially being of benefit for effectively alleviating age-related diseases and disorders, including acute infections and their consequences in elderly or chronically ill patients.

      DIAGNOSIS

       PASC/post-COVID/Long-Haulers/Long-COVID

      The diagnosis of Long-Hauler Syndrome remains as elusive as agreement about a name for the condition. Currently there is no universal definition of the condition or any generally accepted diagnostic algorithm. Compounding matters, there are no specific, objective, consistent markers of pathology. Anecdotally, symptom patterns, combined with documented positive polymerase chain reaction tests for the SARS-COV-2 virus or antibody titers against COVID-19, have been used in practice.
      • Vanichkachorn G
      • Newcomb R
      • Cowl CT
      • et al.
      Post-COVID-19 syndrome (Long Haul syndrome): description of a multidisciplinary clinic at mayo clinic and characteristics of the initial patient cohort.
      However, despite an increasing number of patients obtaining care, the presentation of Long-Hauler Syndrome across diverse age groups, socioeconomic tiers, and ethnicities is not yet well documented, rendering diagnostic or prognostic reliance on these symptom constellations less than ideal.

       Blood SASP factors are increased in Long-Hauler Syndrome

      Factors including IL-6, IL-8, and IP-10, which are also SASP components, appear to predict the severity of acute COVID-19 infection.
      • Laing AG
      • Lorenc A
      • Del Molino Del Barrio I
      • et al.
      Author correction: a dynamic COVID-19 immune signature includes associations with poor prognosis.
      Leukocytes can remain persistently infected by COVID-19, meaning inflammation can persist after the initial infection and acute symptom onset.
      • Troyer EA
      • Kohn JN
      • Hong S.
      Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and potential immunologic mechanisms.
      ,
      • Arbour N
      • Day R
      • Newcombe J
      • Talbot PJ.
      Neuroinvasion by human respiratory coronaviruses.
      ,
      • Desforges M
      • Miletti TC
      • Gagnon M
      • Talbot PJ.
      Activation of human monocytes after infection by human coronavirus 229E.
      As indicated above, once above a threshold, senescent cells may persist or even continue to accumulate. Thus, persistence of senescent cells could contribute to innate immune dysfunction in Long-Haulers syndrome patients, and perhaps even contribute to persistence of virus, further compounding Long-Haulers syndrome. However, in one study, patients with mild Long-Haulers syndrome at least a month after acute COVID-19 infection did not have consistent increases in inflammatory mediators compared to controls who did not have fatigue and generalized pain after acute COVID-19.
      • Scherlinger M
      • Felten R
      • Gallais F
      • et al.
      Refining "long-COVID" by a prospective multimodal evaluation of patients with long-term symptoms attributed to SARS-CoV-2 infection.
      In preliminary studies, we observed increases in markers of cellular senescence and certain SASP factors in patients with more severe Long-Hauler Syndrome that persisted for several months compared to controls (unpublished observations). More study is needed to determine if there are relations between senescence, innate immune dysfunction, and Long-Haulers syndrome. This is particularly important for understanding disease mechanisms in those with severe, persistent symptoms.

      MANAGEMENT

       Long-Haulers clinic—multilevel, patient-centered team-based care

      Patients with Long-Hauler Syndrome present with a multitude of symptoms, the most prominent being profound fatigue, shortness of breath, subjective cognitive complaints, described as “brain fog,” and neurological symptoms consistent with autonomic neuropathy.
      • Vanichkachorn G
      • Newcomb R
      • Cowl CT
      • et al.
      Post-COVID-19 syndrome (Long Haul syndrome): description of a multidisciplinary clinic at mayo clinic and characteristics of the initial patient cohort.
      This broad spectrum of ailments necessitates a multidisciplinary approach to care. One established program at a major academic medical center has successfully treated patients with Long-Hauler Syndrome by coalescing experts from occupational medicine, neurology, physical medicine and rehabilitation, immunology, and specialists in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
      Care can be divided into 5 distinct levels (Fig 1). The first focuses on assessment for complicating medical conditions, such as deep vein thrombosis and opportunistic infections. Once acute medical pathology has been ruled out, the next level of treatment guides patients through an individualized, paced activity program, often supervised by physical and occupational therapists. Medications may be used to control symptoms that interfere with activity and reconditioning, such as tachycardia, insomnia, and cough. The third level of treatment is psychosocial support. This is especially important as roughly 25% of patients have reported difficulties with anxiety and depression during Long-Hauler Syndrome, even without a pre-existing history of mental health conditions. The final 2 levels of treatment use specialist clinics for autonomic dysfunction and concussion to help with dysautonomia symptoms and subjective impaired cognition, respectively. In addition, patients can be educated about coping strategies that allow them to manage their condition best as they progress through the recovery process, which often takes 6-18 months.
      Fig 1
      Fig 1Care for Long-Haulers Syndrome patients is provided through a coordinated 5-level approach, each level designed to treat different subsets of symptoms.

       Geroscience interventions

      The quest for interventions to alleviate age-related dysfunction and diseases has recently intensified, with the focus aimed at prolonging healthspan and alleviating chronic diseases linked to fundamental aging processes, rather than life span at all costs. Currently, among the more promising geroscience interventions are senotherapeutics (senolytics and senomorphics, including metformin and rapalogs), NAD+ precursors, other pharmaceuticals, exercise, and dietary interventions (Fig 2).
      Fig 2
      Fig 2Based on Unitary Theory of Fundamental Aging Mechanisms, all 9 pillars of aging are interdependent and impact one another. Intervening with Geroscience Interventions against any one aging process may have an impact on several, if not all the other aging mechanisms, suggesting a role for multiple treatment targets for age-related diseases.
      There are clinical trials underway testing the efficacy of pharmaceuticals that target the pillars of aging. Senolytics, agents that selectively eliminate senescent cells, have had promising effects in preclinical and early phase clinical trials. As discussed above, senescent cells accumulate in tissues with aging and at etiological sites of multiple chronic diseases and disorders, even in children. Senolytics help attenuate senescent cell burden to below the threshold needed for the immune system to effectively clear remaining senescent cells.
      Also targeting senescent cells, senomorphics inhibit the SASP and so block harmful effects of those senescent cells with a SASP.
      • Farr JN
      • Khosla S.
      Cellular senescence in bone.
      Among senomorphic compounds are Metformin and Rapamycin and its analogs.
      • Birch J
      • Gil J.
      Senescence and the SASP: many therapeutic avenues.
      Used primarily to treat diabetes, Metformin has been shown to impact several aging related mechanisms, including reducing ROS and DNA damage, decreasing senescent cell burden, and activating AMPK, so inhibiting effects of increased mTOR activity.
      • Barzilai N
      • Crandall JP
      • Kritchevsky SB
      • Espeland MA.
      Metformin as a tool to target aging.
      • Algire C
      • Moiseeva O
      • Deschenes-Simard X
      • et al.
      Metformin reduces endogenous reactive oxygen species and associated DNA damage.
      • Barzilai N
      • Huffman DM
      • Muzumdar RH
      • Bartke A.
      The critical role of metabolic pathways in aging.
      Metformin has been explored in preclinical models and is currently being tested in clinical trials as a possible intervention for age-related disorders.
      • Kulkarni AS
      • Gubbi S
      • Barzilai N.
      Benefits of metformin in attenuating the hallmarks of aging.
      There are indications of links between Metformin use and decreased severity of acute COVID-19 infection.
      • Tamura RE
      • Said SM
      • de Freitas LM
      • Rubio IGS.
      Outcome and death risk of diabetes patients with Covid-19 receiving pre-hospital and in-hospital metformin therapies.
      • Blanc F
      • Waechter C
      • Vogel T
      • et al.
      Therapeutic prevention of COVID-19 in elderly: a case-control study.
      • Yang W
      • Sun X
      • Zhang J
      • Zhang K.
      The effect of metformin on mortality and severity in COVID-19 patients with diabetes mellitus.
      Rapamycin and its analogs, rapalogs such as Everolimus or Sirolimus, inhibit mTOR.
      • Blagosklonny MV.
      From rapalogs to anti-aging formula.
      ,
      • Lamming DW
      • Ye L
      • Sabatini DM
      • Baur JA.
      Rapalogs and mTOR inhibitors as anti-aging therapeutics.
      Rapamycin inhibits hyperfunction of the immune system.
      • Blagosklonny MV.
      From causes of aging to death from COVID-19.
      Rapamycin has been approved to treat lymphangioleiomyomatosis, an invasive lung disease
      • McCormack FX
      • Inoue Y
      • Moss J
      • et al.
      Efficacy and safety of sirolimus in lymphangioleiomyomatosis.
      and has been shown to extend healthspan and lifespan in mice.
      • Blagosklonny MV.
      From causes of aging to death from COVID-19.
      ,
      • Blagosklonny MV.
      Rapamycin extends life- and health span because it slows aging.
      Some have suggested that long-term preventative usage of Rapamycin might decrease COVID-19 vulnerability and mortality in the elderly.
      • Blagosklonny MV.
      From causes of aging to death from COVID-19.
      Furthermore, as an mTOR inhibitor, Rapamycin might temper the overall immune response to viral infections and decrease cytokine storm.
      • Blagosklonny MV.
      From causes of aging to death from COVID-19.
      ,
      • Mannick JB
      • Morris M
      • Hockey HP
      • et al.
      TORC1 inhibition enhances immune function and reduces infections in the elderly.
      ,
      • Wang CH
      • Chung FT
      • Lin SM
      • et al.
      Adjuvant treatment with a mammalian target of rapamycin inhibitor, sirolimus, and steroids improves outcomes in patients with severe H1N1 pneumonia and acute respiratory failure.
      Senescent cells promote accumulation of the leukocyte ectoenzyme, CD38, which degrades NAD+ and is associated with the age-related decline in NAD+.
      • Chini CCS
      • Peclat TR
      • Warner GM
      • et al.
      CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD(+) and NMN levels.
      ,
      • Camacho-Pereira J
      • Tarrago MG
      • Chini CCS
      • et al.
      CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism.
      Decreased NAD+, in turn, can lead to generation of ROS and metabolic dysfunction.
      • Hong G
      • Zheng D
      • Zhang L
      • et al.
      Administration of nicotinamide riboside prevents oxidative stress and organ injury in sepsis.
      ,
      • Tarantini S
      • Valcarcel-Ares MN
      • Toth P
      • et al.
      Nicotinamide mononucleotide (NMN) supplementation rescues cerebromicrovascular endothelial function and neurovascular coupling responses and improves cognitive function in aged mice.
      Removal of senescent cells by senolytics leads to reduced CD38 activity, and as a result, partially prevents NAD+ depletion.
      • Chini CCS
      • Peclat TR
      • Warner GM
      • et al.
      CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD(+) and NMN levels.
      Besides senolytics including flavonoids, other pharmacological interventions targeting the age-related increase in CD38 activity include anti-CD-38 antibodies and CD38 inhibitors.
      • Chini EN
      • Chini CCS
      • Espindola Netto JM
      • de Oliveira GC
      • van Schooten W
      The pharmacology of CD38/NADase: an emerging target in cancer and diseases of aging.
      Another option to counter the decline of NAD+ with aging is NAD replacement therapy with NAD+ precursors, including nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN).
      • Camacho-Pereira J
      • Tarrago MG
      • Chini CCS
      • et al.
      CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism.
      ,
      • Schultz MB
      • Sinclair DA.
      Why NAD(+) declines during aging: it's destroyed.
      Resveratrol, a sirtuin agonist and polyphenol, has antioxidant properties and is found in common foods including grapes, red wine, and peanuts.
      • Marinella MA.
      Indomethacin and resveratrol as potential treatment adjuncts for SARS-CoV-2/COVID-19.
      It appears to have antiviral properties both in vivo and in vitro, including inhibiting replication of the COVID-19-like MERS-CoV virus.
      • Marinella MA.
      Indomethacin and resveratrol as potential treatment adjuncts for SARS-CoV-2/COVID-19.
      • Zhao X
      • Tong W
      • Song X
      • et al.
      Antiviral Effect of Resveratrol in Piglets Infected with Virulent Pseudorabies Virus.
      • Lin SC
      • Ho CT
      • Chuo WH
      • Li S
      • Wang TT
      • Lin CC
      Effective inhibition of MERS-CoV infection by resveratrol.
      Thus, resveratrol might be a possible therapeutic option against SARS-CoV-2.
      • Lin SC
      • Ho CT
      • Chuo WH
      • Li S
      • Wang TT
      • Lin CC
      Effective inhibition of MERS-CoV infection by resveratrol.
      17α-estradiol, in contrast to 17β-estradiol, is an essentially nonfeminizing estrogen that is present in both male and female mammals.
      • Gonzalez-Freire M
      • Diaz-Ruiz A
      • de Cabo R.
      17alpha-estradiol: a novel therapeutic intervention to target age-related chronic inflammation.
      ,
      • Courant F
      • Aksglaede L
      • Antignac JP
      • et al.
      Assessment of circulating sex steroid levels in prepubertal and pubertal boys and girls by a novel ultrasensitive gas chromatography-tandem mass spectrometry method.
      It declines with aging. 17α-estradiol treatment might alleviate some neurodegenerative disorders and has been shown to extend lifespan in mice and reduce metabolic dysfunction.
      • Toran-Allerand CD
      • Tinnikov AA
      • Singh RJ
      Nethrapalli IS. 17alpha-estradiol: a brain-active estrogen?.
      • Mann SN
      • Hadad N
      • Nelson HM
      • et al.
      Health benefits attributed to 17alpha-estradiol, a lifespan-extending compound, are mediated through estrogen receptor alpha.
      • Stout MB
      • Steyn FJ
      • Jurczak MJ
      • et al.
      17alpha-estradiol alleviates age-related metabolic and inflammatory dysfunction in male mice without inducing feminization.
      This steroid might be an intervention option for long-term impacts of COVID.
      Ketogenic diets and ketogenic agents reduce fat mass and obesity, one of the major risk factors for COVID-19 complications.
      • Paoli A
      • Gorini S
      • Caprio M.
      The dark side of the spoon - glucose, ketones and COVID-19: a possible role for ketogenic diet?.
      ,
      • Gangitano E
      • Tozzi R
      • Gandini O
      • et al.
      Ketogenic diet as a preventive and supportive care for COVID-19 patients.
      Ketogenic diets and agents could also help modulate the cytokine storm by decreasing ROS through an increase in mitochondrial metabolism. Ketogenic diets have shown promise in mouse models as a potential treatment against morbidity from viral infections.
      • Bradshaw PC
      • Seeds WA
      • Miller AC
      • Mahajan VR
      • Curtis WM.
      COVID-19: proposing a ketone-based metabolic therapy as a treatment to blunt the cytokine storm.
      • Sukkar SG
      • Bassetti M.
      Induction of ketosis as a potential therapeutic option to limit hyperglycemia and prevent cytokine storm in COVID-19.
      • Ryu S
      • Shchukina I
      • Youm YH
      • et al.
      Ketogenesis restrains aging-induced exacerbation of COVID in a mouse model.
      Other dietary modifications, such as caloric restriction (CR) and intermittent fasting (IF), have also been shown to be effective therapies against age-related disease and dysfunction.
      • Lopez-Lluch G
      • Navas P.
      Calorie restriction as an intervention in ageing.
      • Mattson MP
      • Longo VD
      • Harvie M.
      Impact of intermittent fasting on health and disease processes.
      • Madeo F
      • Carmona-Gutierrez D
      • Hofer SJ
      • Kroemer G.
      Caloric restriction mimetics against age-associated disease: targets, mechanisms, and therapeutic potential.
      IF consists of an alternating feeding schedule, whereas CR limits daily caloric intake without malnutrition. CR and IF reduce oxidative stress and inflammation.
      • Madeo F
      • Carmona-Gutierrez D
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       Trials of senolytics

      Multiple clinical trials are currently underway to investigate a potential role for senolytics in COVID-19 infection in older adults. COVID-FIS (A Phase 2 Placebo-Controlled Pilot Study in COVID-19 of Fisetin to Alleviate Dysfunction and Excessive Inflammatory Response in Older Adults in Nursing Homes; NIH R01AG72301; FDA IND149813; ClinicalTrials.gov Identifier: NCT04537299) includes SNF residents aged > 65 years who have tested positive for COVID-19 by rtPCR and have oxygen saturation >85% on 2 liters/minute or less of supplemental oxygen. Exclusion criteria are designed to preserve eligibility for most SNF residents, even those with several chronic diseases and polypharmacy, and do not exclude potential participants due to use of other agents to treat COVID-19 infection, either previously to or concurrently with Fisetin. Participants are randomized 1:1 to receive either Fisetin (∼20 mg/kg/day) or placebo either orally or by NG or D tube twice for 2 consecutive days (days 0, 1, 8, and 9). They are followed for 6 months. Facilitating administration to older adults, including those with swallowing dysfunction, both Fisetin and the placebo have no odor or taste, and can be mixed with food or beverages. The primary outcome of the COVID-FIS study is incidence of progression on a 7-point ordinal severity scale adapted from the WHO Ordinal Scale for clinical improvement of SARS-CoV-2. Secondary outcomes include measures of senescent cell abundance/inflammation, physical dysfunction/frailty, safety/tolerability, various laboratory parameters, chest imaging, need for acute hospital transfer, ICU care, intubation, mortality, and development of Long-Hauler syndrome.
      COVID-FISETIN (A Phase 2 Placebo-Controlled Pilot Study in COVID-19 of Fisetin to Alleviate Dysfunction and Excessive Inflammatory Response in Hospitalized Adults; NIH R01AG72301; FDA IND149813; ClinicalTrials.gov Identifier: NCT04476953) is an analogous trial targeting adults who are hospitalized with COVID-19 infection. Eligible individuals are those aged ≥ 60 years (or age ≥ 18-59 years with at least one comorbidity that is associated with increased COVID-19 disease severity) who are hospitalized with COVID-19 infection and have SpO2 ≥ 85% on room air or ≤ 2 L of supplemental oxygen. Participants are randomized 1:1 to receive either Fisetin (∼20 mg/kg/day) or placebo either orally or by NG or D tube for 2 consecutive days at study outset and are subsequently followed for 6 months. The primary outcome is oxygenation status as measured by S/F ratio: SpO2/ FiO2. Secondary outcomes include prevention of deterioration in physical function (frailty), progression from mild/moderate to severe/critical infection, safety and tolerability of Fisetin, and development of Long-Hauler syndrome.

       Combining therapies

      Building on the Geroscience Hypothesis and importance of intervening at a mechanistic level, our Unitary Theory of Fundamental Aging Mechanisms posits that interventions against one aging mechanism might impact other processes. Combining geroscience interventions to fight COVID-19 as a multimechanistic approach might improve outcomes for older adults.

      CONCLUSIONS AND FUTURE DIRECTIONS

       Research needed—specific areas requiring future investigation

      While senescence and other pillars of aging provide reasonable insight into the possible processes involved and risks for Long-Hauler Syndrome, detailed mechanisms of the SARS-CoV-2 and its impact on older adults need to be further explored. Furthermore, therapeutics specifically targeting those mechanism need to be tested in clinical trials.
      The Translational Geroscience Network (TGN) was established to accelerate Geroscience research. Multiple institutions that constitute the TGN (Mayo Clinic, Harvard, John Hopkins, Wake Forrest, St. Jude's, Steadman Clinic, and the Universities of Minnesota, Michigan, and Connecticut, and the University of Texas Health Sciences Center at San Antonio) run clinical trials in parallel. The TGN's Facility for Geroscience Analysis (FGA), located at Mayo Clinic, develops innovative assays and laboratory tests for aging markers and ways to test for efficacy of therapeutics. Hopefully, despite considerable barriers to clinical trials, the TGN model will help streamline clinical research and the development of therapeutics for a growing aging population, including SNF residents.
      As the number of people impacted globally by COVID-19 grows each day and the SARS-CoV-2 evolves into new variants, it is imperative for research efforts to keep up. Though knowledge about long-term outcomes of COVID-19 is still limited, we know enough to understand the importance of finding treatment options for patients suffering from Long-Hauler Syndrome. Senolytics that show early promise as an effective treatment for other senescence related diseases and disorders are currently being explored in this population.

      Acknowledgments

      Conflicts of Interest: TT and JLK have a financial interest related to this research. Patents and pending patents on senolytic drugs and their uses are held by Mayo Clinic. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and was conducted in compliance with Mayo Clinic Conflict of Interest policies. No conflicts of interest, financial or otherwise, are declared by the other authors. This manuscript has been reviewed by and approved by all named authors, and all authors have read the journal's authorship agreement.
      This work was supported by NIH grants R01AG072301 (PI: JLK), R33AG61456 ( Translational Geroscience Network ; PI: JLK), R37AG013925 (JLK, TT), and P01AG062413 (JLK, TT), the Connor Fund (JLK, TT), Robert P. and Arlene R. Kogod (JLK), Robert J. and Theresa W. Ryan (JLK, TT), and the Noaber Foundation (JLK, TT).

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