Dysregulated nicotinamide adenine dinucleotide metabolome in patients hospitalized with COVID-19.

Nicotinamide adenine dinucleotide (NAD+) depletion has been postulated as a contributor to the severity of COVID-19; however, no study has prospectively characterized NAD+ and its metabolites in relation to disease severity in patients with COVID-19. We measured NAD+ and its metabolites in 56 hospitalized patients with COVID-19 and in two control groups without COVID-19: (1) 31 age- and sex-matched adults with comorbidities, and (2) 30 adults without comorbidities. Blood NAD+ concentrations in COVID-19 group were only slightly lower than in the control groups (p < 0.05); however, plasma 1-methylnicotinamide concentrations were significantly higher in patients with COVID-19 (439.7 ng/mL, 95% CI: 234.0, 645.4 ng/mL) than in age- and sex-matched controls (44.5 ng/mL, 95% CI: 15.6, 73.4) and in healthy controls (18.1 ng/mL, 95% CI 15.4, 20.8; p < 0.001 for each comparison). Plasma nicotinamide concentrations were also higher in COVID-19 group and in controls with comorbidities than in healthy control group. Plasma concentrations of 2-methyl-2-pyridone-5-carboxamide (2-PY), but not NAD+, were significantly associated with increased risk of death (HR = 3.65; 95% CI 1.09, 12.2; p = 0.036) and escalation in level of care (HR = 2.90, 95% CI 1.01, 8.38, p = 0.049). RNAseq and RTqPCR analyses of PBMC mRNA found upregulation of multiple genes involved in NAD+ synthesis as well as degradation, and dysregulation of NAD+-dependent processes including immune response, DNA repair, metabolism, apoptosis/autophagy, redox reactions, and mitochondrial function. Blood NAD+ concentrations are modestly reduced in COVID-19; however, NAD+ turnover is substantially increased with upregulation of genes involved in both NAD+ biosynthesis and degradation, supporting the rationale for NAD+ augmentation to attenuate disease severity.

Mitochondrial heterogeneity and crosstalk in aging: Time for a paradigm shift?

The hallmarks of aging have been influential in guiding the biology of aging research, with more recent and growing recognition of the interdependence of these hallmarks on age-related health outcomes. However, a current challenge is personalizing aging trajectories to promote healthy aging, given the diversity of genotypes and lived experience. We suggest that incorporating heterogeneity-including intrinsic (e.g., genetic and structural) and extrinsic (e.g., environmental and exposome) factors and their interdependence of hallmarks-may move the dial. This editorial perspective will focus on one hallmark, namely mitochondrial dysfunction, to exemplify how consideration of heterogeneity and interdependence or crosstalk may reveal new perspectives and opportunities for personalizing aging research. To this end, we highlight heterogeneity within mitochondria as a model.

Poor sleep quality is linked to increased frailty in middle-aged people living with HIV in Botswana.

This work aims to evaluate associations between self-reported sleep health and frailty in Botswana, a sub-Saharan Africa setting. Fifty persons living with HIV (PLWH) on suppressive antiretroviral therapy (ART) and fifty HIV seronegative control participants are enrolled in Botswana. Sleep quality is scored subjectively as "good" or "poor" based on self-report. A frailty index (FI) is constructed based on thirty-three health deficits related to body mass index, waist circumference, physical activity, emotional status, and fatigue, and scored ranging between 0 (no deficit present) and 1 (all deficits present). Sleep quality between PLWH and controls is compared using logistic regression; linear regression is performed to compare the FI between them. Linear regressions are performed to examine the association between the FI and sleep quality stratified by HIV serostatus. Age, sex, and comorbidities are adjusted; when relevant, CD4 cell and ART duration are controlled. PLWH display 2.88 (95% CI: 1.22-6.79, p = 0.02) higher odds of having poor sleep than controls. Having poor sleep is associated with increased FI in PLWH but not in controls. Specifically, compared with PLWH who have good sleep, PLWH who report poor sleep have a > 1 standard deviation (p < 0.0001) increase in their FI score.

Enabling translational geroscience by broadening the scope of geriatric care.

Geroscience poses that core biological mechanisms of aging contribute to chronic diseases and disabilities in late life and that health span and longevity can be modulated by pharmacological and behavioral interventions. Despite strong evidence from studies in model organisms and great potentials for translation, most geriatricians remain skeptical that geroscience will help them in the day-by-day battle with the consequences of aging in their patients. We believe that a closer collaboration between gerontologists and geriatricians is the key to overcome this impasse. There is evidence that trajectories of health with aging are rooted in intrinsic and extrinsic exposures that occur early in life and affect the pace of molecular and cellular damage accumulation with aging, also referred to as the "pace" of biological aging. Tools that measure the pace of aging currently allow for the identification of individuals experiencing accelerated aging and at higher risk of multimorbidity and disability. What we term "Translational Geroscience", i.e., the merger of fundamental and translational science with clinical practice, is thus poised to extend the action of geriatric care to a life course perspective. By targeting core mechanisms of aging, gerotherapeutics should be effective in treating patients with multimorbidity and disability, phenotypes that are all too common among geriatric patients nowadays. We call for initiatives that enhance the flow of ideas between gerontologists and geriatricians to facilitate the growth of translational geroscience. This approach can widen the scope of geriatric care, including a new role for geroscience in the promotion and operationalization of healthy longevity.

Healthy aging: Linking causal mechanisms with holistic outcomes.

Identifying and understanding the impact of differing exposures over the lifecourse necessitates contextualizing different levels of influence ranging from genetics, epigenetics, geography, and psychosocial networks.

Can statin preventative treatment inform geroscience-guided therapeutics?

Potential senotherapeutic effect of statins may lead to prevention and reduction of frailty.

Maladaptive Immune Activation in Age-Related Decline of Muscle Function.

Age-related changes in immune competency and inflammation play a role in the decline of physical function. In this review of the conference on Function-Promoting Therapies held in March 2022, we discuss the biology of aging and geroscience with an emphasis on decline in physical function and the role of age-related changes in immune competence and inflammation. More recent studies in skeletal muscle and aging highlighting a crosstalk between skeletal muscle, neuromuscular feedback, and immune cell subsets are also discussed. The value of strategies targeting specific pathways that affect skeletal muscle and more systems-wide approaches that provide benefits in muscle homeostasis with aging are underscored. Goals in clinical trial design and the need for incorporating differences in life history when interpreting results from these intervention strategies are important. Where applicable, references are made to papers presented at the conference. We conclude by underscoring the need to incorporate age-related immune competency and inflammation when interpreting results from interventions that target specific pathways predicted to promote skeletal muscle function and tissue homeostasis.

Multi-modal profiling of peripheral blood cells across the human lifespan reveals distinct immune cell signatures of aging and longevity.

BACKGROUND: Age-related changes in immune cell composition and functionality are associated with multimorbidity and mortality. However, many centenarians delay the onset of aging-related disease suggesting the presence of elite immunity that remains highly functional at extreme old age. METHODS: To identify immune-specific patterns of aging and extreme human longevity, we analyzed novel single cell profiles from the peripheral blood mononuclear cells (PBMCs) of a random sample of 7 centenarians (mean age 106) and publicly available single cell RNA-sequencing (scRNA-seq) datasets that included an additional 7 centenarians as well as 52 people at younger ages (20-89 years). FINDINGS: The analysis confirmed known shifts in the ratio of lymphocytes to myeloid cells, and noncytotoxic to cytotoxic cell distributions with aging, but also identified significant shifts from CD4+ T cell to B cell populations in centenarians suggesting a history of exposure to natural and environmental immunogens. We validated several of these findings using flow cytometry analysis of the same samples. Our transcriptional analysis identified cell type signatures specific to exceptional longevity that included genes with age-related changes (e.g., increased expression of STK17A, a gene known to be involved in DNA damage response) as well as genes expressed uniquely in centenarians' PBMCs (e.g., S100A4, part of the S100 protein family studied in age-related disease and connected to longevity and metabolic regulation). INTERPRETATION: Collectively, these data suggest that centenarians harbor unique, highly functional immune systems that have successfully adapted to a history of insults allowing for the achievement of exceptional longevity. FUNDING: TK, SM, PS, GM, SA, TP are supported by NIH-NIAUH2AG064704 and U19AG023122. MM and PS are supported by NIHNIA Pepper center: P30 AG031679-10. This project is supported by the Flow Cytometry Core Facility at BUSM. FCCF is funded by the NIH Instrumentation grant: S10 OD021587.

Epigenetic Age Acceleration Markers Are Associated With Physiologic Frailty and All-Cause Mortality in People With Human Immunodeficiency Virus.

BACKGROUND: Biomarkers that provide insight into drivers of aging are needed for people with human immunodeficiency virus (PWH). The study objective was to determine if epigenetic age acceleration (EAA) markers are associated with physiologic frailty measured by the Veterans Aging Cohort Study (VACS) Index and predict all-cause mortality for PWH. METHODS: Epigenome-wide DNA methylation was profiled in VACS total white blood cell samples collected during 2005-2007 from 531 PWH to generate 6 established markers of EAA. The association of each EAA marker was tested with VACS Index 2.0. All-cause mortality was assessed over 10 years. For each EAA marker, the hazard ratio per increased year was determined using Cox regression. To evaluate mortality discrimination, C-statistics were derived. RESULTS: Participants were mostly men (98.5%) and non-Hispanic Black (84.4%), with a mean age of 52.4 years (standard deviation [SD], 7.8 years). Mean VACS Index score was 59.3 (SD, 16.4) and 136 deaths occurred over a median follow-up of 8.7 years. Grim age acceleration (AA), PhenoAA, HannumAA, and extrinsic epigenetic AA were associated with the VACS Index and mortality. HorvathAA and intrinsic epigenetic AA were not associated with either outcome. GrimAA had the greatest mortality discrimination among EAA markers and predicted mortality independently of the VACS Index. One-year increase in GrimAA was associated with a 1-point increase in VACS Index and a 10% increased hazard for mortality. CONCLUSIONS: The observed associations between EAA markers with physiologic frailty and mortality support future research to provide mechanistic insight into the accelerated aging process and inform interventions tailored to PWH for promoting increased healthspan.

Biological ageing with HIV infection: evaluating the geroscience hypothesis.

Although people with HIV are living longer, as they age they remain disproportionately burdened with multimorbidity that is exacerbated in resource-poor settings. The geroscience hypothesis postulates that a discrete set of between five and ten hallmarks of biological ageing drive multimorbidity, but these processes have not been systematically examined in the context of people with HIV. We examine four major hallmarks of ageing (macromolecular damage, senescence, inflammation, and stem-cell dysfunction) as gerodrivers in the context of people with HIV. As a counterbalance, we introduce healthy ageing, physiological reserve, intrinsic capacity, and resilience as promoters of geroprotection that counteract gerodrivers. We discuss emerging geroscience-based diagnostic biomarkers and therapeutic strategies, and provide examples based on recent advances in cellular senescence, and other, non-pharmacological approaches. Finally, we present a conceptual model of biological ageing in the general population and in people with HIV that integrates gerodrivers and geroprotectors as modulators of homoeostatic reserves and organ function over the lifecourse.

Geriatric Conditions Associated with Nonadherence to Antiretroviral Therapy Among Older People with HIV: The Importance of Frailty.

Poor compliance with medications is a growing concern in geriatric care and is increasingly more relevant among people living with HIV (PLWH) as they age. Our goal was to understand geriatric conditions associated with antiretroviral therapy (ART) nonadherence in a Medicare population of older PLWH. We analyzed Medicare data from PLWH aged 50 years or older who were continuously enrolled in fee-for-service Medicare from January 1, 2014 to June 30, 2015. Prevalent geriatric conditions (dementia, depression, falls, hip fracture, sensory deficits, osteoporosis, orthostatic hypotension, urinary incontinence, frailty) were identified in January 1, 2014-December 31, 2014. ART nonadherence was defined as <80% proportion of days covered (PDC) by at least two ART medications in January 1, 2015-June 30, 2015. We examined geriatric condition association with nonadherence using lowest Akaike Information Criterion multi-variate logistic models, controlling for age, sex, race, census region, substance use, Medicaid eligibility, and polypharmacy. Of 8778 PLWH, 23% (n = 2042) had <80% PDC. The average age was 60 years (standard deviation ±8), and >70% were males. In adjusted models, age was not associated with nonadherence, frailty status was the only geriatric condition associated with nonadherence [robust: reference, prefrail odds ratio (OR): 0.97, confidence interval (95% CI) 0.86-1.10, frail OR: 1.34 95% CI 1.11-1.61], and odds of nonadherence were lower for polypharmacy [OR: 0.48 (0.43-0.54)]. Our findings suggest that patient-centered care plans aimed at improving ART adherence among older PLWH would benefit from long-term surveillance; a deeper understanding of the role of frailty and polypharmacy, even at chronologically younger ages in PLWH.