Citations

Abstract There are no circulating markers exclusive to cell senescence for clinical trials in middle-aged/older adults. In this study we evaluated T-cell expression of tumor suppressor protein p16INK4a and plasma senescence associated secretory proteins (SASP)-factors in the context of an 18-week randomized trial of caloric restriction (CR) compared to a weight stable Control. The analysis includes 55 middle-aged/older adults (75%Women; 33%African American; 57.6±5.8 years) with obesity and prediabetes. We measured mRNA expression of select senescence and apoptosis gene transcripts (p16INK4a, p21, BCL2L, BAK1) in peripheral blood CD3+ T-cells (quantitative-RT-PCR) and a panel of 27 plasma SASP proteins (Luminex/multiplex; ELISA). Weight loss in those randomized to CR was -10.8±0.9 kg compared to +0.5±0.9 kg in Control. Using mixed models, T-cell expression of senescence-biomarkers p16INK4a, p21, BCL-2L, and apoptosis-marker BAK1 were not different between CR and control at 18 weeks (time × treatment adjusted for age, race, and sex, all p>0.05). We explored associations between biomarkers with weight loss; moderate spearman correlations (rs=0.28 to 0.64) were observed between weight loss and change in plasma SASP-factors (Activin A, I-CAM, MMP1, PAI-1, TNF-RI, TNF-RII, VEGF, uPAR, p< 0.05 all), but not T-cell biomarker expression. We evaluated associations between biomarkers and found change in T-cell p16INK4a was associated with change in plasma SASP-factors, Fas (rs=0.51), osteopontin (rs=0.34), myeloperoxidase (rs=0.39), and MMP2 (rs=0.40) (CR+Control combined). Among middle-aged/older persons with obesity undergoing 18-weeks CR, changes in T cell p16INK4a expression were correlated with reductions in key SASP factors, and weight loss was associated with lower pro-inflammatory SASP profile.

Abstract Skeletal muscle aging is marked by the loss and atrophy of resident fibers, and the accumulation of functionally diverse cell types including fibroblasts, adipocytes, and immune cells. Senescent cells amass in multiple tissues with advancing age where they contribute to aging, chronic disease, and physical decline. The role of senescence in mediating muscle aging has become a popular and sometimes contentious topic. However, to date, this concept has not been methodically tested. In this study, we characterized the changes in cell abundance and, importantly, cell-specific transcriptional profiles with skeletal muscle aging using scRNAseq. Interestingly, we identified a small population of p16 positive fibro-adipogenic progenitors (FAPs) which, upon further investigation using immunohistochemical methods, were found to express other senescence markers. This subpopulation of FAPs did not exhibit elevation in p21 levels with age. Instead, terminally differentiated myofibers were the source of the p21 increase. Myofibers with high p21 expression exhibit a strong inflammatory phenotype, which includes activated p53 signaling pathways together with strong cytokine-cytokine receptor interactions. We further identified large amounts of cross-talk between different cell types, suggesting that senescent FAPs and myofibers could contribute to skeletal muscle aging in a paracrine manner. Importantly, these observations in mice were confirmed in human samples, suggesting the strong translational power of these findings.

Abstract Skeletal muscle aging is marked by the loss and atrophy of resident fibers, and the accumulation of functionally diverse cell types including fibroblasts, adipocytes, and immune cells. Senescent cells amass in multiple tissues with advancing age where they contribute to aging, chronic disease, and physical decline. The role of senescence in mediating muscle aging has become a popular and sometimes contentious topic. However, to date, this concept has not been methodically tested. In this study, we characterized the changes in cell abundance and, importantly, cell-specific transcriptional profiles with skeletal muscle aging using scRNAseq. Interestingly, we identified a small population of p16 positive fibro-adipogenic progenitors (FAPs) which, upon further investigation using immunohistochemical methods, were found to express other senescence markers. This subpopulation of FAPs did not exhibit elevation in p21 levels with age. Instead, terminally differentiated myofibers were the source of the p21 increase. Myofibers with high p21 expression exhibit a strong inflammatory phenotype, which includes activated p53 signaling pathways together with strong cytokine-cytokine receptor interactions. We further identified large amounts of cross-talk between different cell types, suggesting that senescent FAPs and myofibers could contribute to skeletal muscle aging in a paracrine manner. Importantly, these observations in mice were confirmed in human samples, suggesting the strong translational power of these findings.

Abstract New strategies to preserve cognitive function could broadly benefit the aging population. Cellular senescence is a hypothesized mediator of inflammation-related tissue dysfunction in aging. Using single-cell RNA-sequencing, we discovered an age-related brain myeloid population exhibiting overlapping senescent and disease-associated activation signatures, including upregulation of chemoattractant factors. We confirmed senescent brain myeloid cells promote peripheral immune cell chemotaxis in vitro. Through mass cytometry, we demonstrate age- and sex-dependent increases in activated resident and infiltrating brain immune cells are reduced through systemic targeting of p16-positive senescent cells, which is associated with improvements in executive function and spatial learning tasks. Our high-dimensional results reveal dynamic remodeling of the age-dependent brain immune cell landscape and implicate senescent cell targeting as a strategy to counter inflammatory changes and cognitive decline.

Abstract Skeletal muscle aging is marked by the loss and atrophy of resident fibers, and the accumulation of functionally diverse cell types including fibroblasts, adipocytes, and immune cells. Senescent cells amass in multiple tissues with advancing age where they contribute to aging, chronic disease, and physical decline. The role of senescence in mediating muscle aging has become a popular and sometimes contentious topic. However, to date, this concept has not been methodically tested. In this study, we characterized the changes in cell abundance and, importantly, cell-specific transcriptional profiles with skeletal muscle aging using scRNAseq. Interestingly, we identified a small population of p16 positive fibro-adipogenic progenitors (FAPs) which, upon further investigation using immunohistochemical methods, were found to express other senescence markers. This subpopulation of FAPs did not exhibit elevation in p21 levels with age. Instead, terminally differentiated myofibers were the source of the p21 increase. Myofibers with high p21 expression exhibit a strong inflammatory phenotype, which includes activated p53 signaling pathways together with strong cytokine-cytokine receptor interactions. We further identified large amounts of cross-talk between different cell types, suggesting that senescent FAPs and myofibers could contribute to skeletal muscle aging in a paracrine manner. Importantly, these observations in mice were confirmed in human samples, suggesting the strong translational power of these findings.

Abstract Exposure of biological systems to acute or chronic insults triggers a host of molecular and physiological responses to either tolerate, adapt, or fully restore homeostasis; these responses constitute the hallmarks of resilience. Given the many facets, dimensions, and discipline‐specific focus, gaining a shared understanding of “resilience” has been identified as a priority for supporting advances in cardiovascular health. This report is based on the working definition: “ Resilience is the ability of living systems to successfully maintain or return to homeostasis in response to physical, molecular, individual, social, societal, or environmental stressors or challenges ,” developed after considering many factors contributing to cardiovascular resilience through deliberations of multidisciplinary experts convened by the National Heart, Lung, and Blood Institute during a workshop entitled: “ Enhancing Resilience for Cardiovascular Health and Wellness.” Some of the main emerging themes that support the possibility of enhancing resilience for cardiovascular health include optimal energy management and substrate diversity, a robust immune system that safeguards tissue homeostasis, and social and community support. The report also highlights existing research challenges, along with immediate and long‐term opportunities for resilience research. Certain immediate opportunities identified are based on leveraging existing high‐dimensional data from longitudinal clinical studies to identify vascular resilience measures, create a ‘resilience index,’ and adopt a life‐course approach. Long‐term opportunities include developing quantitative cell/organ/system/community models to identify resilience factors and mechanisms at these various levels, designing experimental and clinical interventions that specifically assess resilience, adopting global sharing of resilience‐related data, and cross‐domain training of next‐generation researchers in this field.

Abstract Physical activity (PA) is associated with improvement in breast cancer treatment-related symptoms and survival, yet most breast cancer survivors do not meet national PA guidelines. This study aimed to identify characteristics of participants that were associated with an increased likelihood of meeting PA guidelines. Adults with breast cancer seen at Mayo Clinic (Rochester, MN) were surveyed regarding their PA participation, and those who self-reported at least 150 minutes of moderate and/or strenuous aerobic PA weekly on average were considered to be “meeting guidelines”. Three thousand participants returned PA data. Younger age, completion of the survey 7-12 years after diagnosis, absence of recurrence, no bilateral mastectomy, absence of metastatic disease, and lower BMI at the time of survey completion were associated with PA participation (P < .05 in univariate and multivariate analyses). Findings were similar when a threshold of 90 minutes was applied. These results may inform the development of targeted PA-facilitating interventions.

Objectives To study the association between multi-morbidity percentiles, which is a measure of clinical aging, and interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α. Methods Participants 50 to 95 years of age from the Mayo Clinic Study of Aging were assigned age- and sex-specific multi-morbidity percentiles using look-up tables that were reported previously (n = 1646). Percentiles were divided into quintiles for analysis. Plasma IL-6, IL-10, and TNF-α levels were measured in 1595 participants. Median inflammatory marker levels were compared across multi-morbidity quintiles using nonparametric tests. Results People with higher multi-morbidity percentiles had significantly higher IL-6 and TNF-α levels compared with those with lower multi-morbidity percentiles. Tests for trend across five multi-morbidity quintiles were significant among women for IL-6 and among participants 70 years of age or older for IL-6 and TNF-α. IL-10 was not associated with multi-morbidity percentiles. Conclusions Multi-morbidity percentiles may be a useful clinical index of biological age for future studies, particularly in women and people 70 years of age and older.

We propose the beneficial effects of exercise are in part mediated through the prevention and elimination of senescent cells. Exercise counters multiple forms of age-related molecular damage that initiate the senescence program and activates immune cells responsible for senescent cell clearance. Preclinical and clinical evidence for exercise as a senescence-targeting therapy and areas needing further investigation are discussed.