Findings of post-acute sequelae of Post-COVID Conditions (PCC) manifestations of fatigue, pain, dyspnea, and muscle weakness, provide a strong rationale for rehabilitation; yet few formal studies exist and the effects of severe acute respiratory syndrome coronavirus-2 infection on function are not well described. Notably, two- thirds of Veterans are overweight and obese, rendering excess adiposity a significant risk factor and a high- priority area related to PCC prevention and care. Obesity increases the risk of severe illness in Veterans recovering from PCC, but how it does so is not fully understood. Recent research suggests that excess adipose tissue is associated with adverse changes in adipose cellular function, and that these variations may be involved in the biology of aging and the etiology of aging- related diseases. Adipose tissue contains cells that have undergone cellular senescence, which induces inflammation, cytotoxicity, and metabolic dysfunction in other cells and tissues. However, the precise role of adipose tissue cellular composition on PCC recovery is limited. Thus, we propose to evaluate the role of obesity and PCC on physical functioning, health-related quality of life (HRQOL), and systemic and adipose tissue inflammatory and cellular senescence profiles in ethnically diverse older Veterans from the Audie Murphy (San Antonio) and Baltimore VA Medical Centers. Further, we propose a randomized controlled trial to determine whether a reduction in body weight and increased physical function by a weight loss intervention (WL), including dietary modification and exercise, in obese Veterans with PCC will reduce systemic and adipose tissue inflammation and senescence, which will have important implications for PCC recovery. We will pursue the following aims: Aim 1: To compare physical function, body composition, HRQOL, PCC symptoms, and adipose tissue molecular profiling in four cohorts of Veterans at baseline: lean PCC naïve, lean with PCC, obese PCC naïve, and obese with PCC (N=150). Aim 2: To compare in Veterans with obesity: a) a 12-week randomized WL vs. weight stability (WS) intervention (30/group) on physical function, body composition, HRQOL, and PCC symptoms together with changes in the global molecular profile in adipose tissue in Veterans with PCC and b) the WL intervention in PCC naïve vs. with PCC (N=30/group) on these outcomes. Older (55-80 years) men and women Veterans will be recruited. We will perform a standard functional battery (maximal aerobic capacity [VO2max; primary outcome], usual gait speed, six min walk distance, timed up and go, and handgrip strength), body composition (dual energy x-ray absorptiometry and computed tomography scans), HRQOL (NIH PROMIS-57), and PCC symptoms (COVID-19 Yorkshire Rehabilitation Scale [C19-YRS]) and adipose tissue will be collected. Further, we will test, in a randomized controlled trial, the hypothesis that a WL intervention, compared to weight stability (WS), improves physical function, body composition, and HRQOL and reduces inflammation and senescent cell burden and to a similar extent as the PCC naïve group with obesity. A deeper understanding of the relationship between adipose tissue and PCC will likely reveal factors that predispose to or protect against aging-related functional declines. Moreover, a better understanding of the effects of a lifestyle intervention on the molecular profile of adipose tissue will help to determine how changes in adipose tissue contribute to PCC and PCC recovery. Lastly, this research will provide important mechanistic insights into how cellular senescence influences the pathophysiology of physical, mental, and social dysfunction in older Veterans. Our findings could provide evidence-based recommendations to promote this type of intervention in Veterans recovering from PCC.

The research in this VA Merit will examine the effects of obesity and Post-COVID Conditions (PCC) on physical functioning, health-related quality of life, and adipose tissue inflammatory and cellular senescence profiles in older Veterans. Further, it will evaluate whether a weight loss intervention, including dietary modification and exercise, in obese Veterans with and without PCC will reduce systemic and adipose tissue inflammation and senescence and promote PCC recovery. This research is especially relevant to older Veterans as two-thirds of Veterans are overweight or obese, rendering excess adiposity a significant risk factor and a high- priority area related to COVID-19 prevention and care. This study also will explore potential mechanisms by which systemic and adipose tissue inflammation and senescence influences the pathophysiology of physical, mental, and social dysfunction in older Veterans recovering from COVID-19. Our findings could lead to novel lifestyle and pharmacologic strategies to optimize COVID-19 recovery.