Steven R Cummings’s research while affiliated with University of California, San Francisco and other places

DNA methylation marks have recently been used to build models known as epigenetic clocks, which predict calendar age. As methylation of cytosine promotes C-to-T mutations, we hypothesized that the methylation changes observed with age should reflect the accrual of somatic mutations, and the two should yield analogous aging estimates. In an analysis of multimodal data from 9,331 human individuals, we found that CpG mutations indeed coincide with changes in methylation, not only at the mutated site but with pervasive remodeling of the methylome out to ±10 kilobases. This one-to-many mapping allows mutation-based predictions of age that agree with epigenetic clocks, including which individuals are aging more rapidly or slowly than expected. Moreover, genomic loci where mutations accumulate with age also tend to have methylation patterns that are especially predictive of age. These results suggest a close coupling between the accumulation of sporadic somatic mutations and the widespread changes in methylation observed over the course of life.

Mitochondrial energetics are an important property of aging muscle, as generation of energy is pivotal to the execution of muscle contraction. However, its association with functional outcomes, including leg power and cardiorespiratory fitness, is largely understudied. In the Study of Muscle, Mobility and Aging, we collected vastus lateralis biopsies from older adults (n = 879, 70–94 years, 59.2% women). Maximal State 3 respiration (Max OXPHOS) was assessed in permeabilized fiber bundles by high-resolution respirometry. Capacity for maximal adenosine triphosphate production (ATPmax) was measured in vivo by 31 P magnetic resonance spectroscopy. Leg extension power was measured with a Keiser press system, and VO2peak was determined using a standardized cardiopulmonary exercise test. Gender-stratified multivariate linear regression models were adjusted for age, race, technician/site, adiposity, and physical activity with beta coefficients expressed per 1-SD increment in the independent variable. Max OXPHOS was associated with leg power for both women (β = 0.12 Watts/kg, p <.001) and men (β = 0.11 Watts/kg, p <.050). ATPmax was associated with leg power for men (β = 0.09 Watts/kg, p <.05) but was not significant for women (β = 0.03 Watts/kg, p =.11).

Older adults who self-identify as Black have a disproportionately higher incidence of mobility disability. Whether older adults who are Black also have lower fitness and mitochondrial energetics compared to those who are White has not been adequately investigated. The Study of Muscle, Mobility and Aging (SOMMA) examined 879 older adults (≥70 years old), including 116 who self-identified as Black, who could complete a 400m walk within 15 minutes. Mitochondrial respiration (MaxOXPHOS) was measured in permeabilized fibers from biopsies of the vastus lateralis. A cardiopulmonary exercise test assessed maximum oxygen consumption (VO2peak). Education, income, financial resources, race, sex and age were determined by self-report. Propensity score matching was used to match Blacks with Whites with a 1:1 ratio. Black (n=90) and White (n=90) groups were well matched for age, sex, SOMMA multimorbidity index, BMI, muscle mass, physical activity, marital status, educational achievement, and whether financial needs were met (all p>0.05). Despite being well matched, those who identified as Black had a slower 400m walking speed (0.97 vs. 1.03 m/s, p=0.014), lower MaxOXPHOS (50.8 vs. 60.9 (pmol/(s*mg)), p< 0.001), and lower cardiorespiratory fitness (1391 vs 1566 ml/min, p=0.007), when compared to those who identified as White. Multivariate regression showed that VO2peak and MaxOXPHOS, but not socioeconomic factors, attenuated the race difference in 400m walking speed. In conclusion, while the etiology of race differences in mobility is multifactorial, our data indicate that muscle mitochondrial respiration and cardiorespiratory fitness may contribute to slower walking speed of individuals who identify as Black compared to White.

The geroscience hypothesis proposes that underlying biological processes, such as the accumulation of senescent cells, have deleterious effects on multiple tissues and increase the risk of many chronic conditions with aging. Senescent cells produce heterogenous biomarkers, also called senescence-associated secretory phenotype (SASP). Circulating concentrations of senescence biomarkers may reflect an underlying burden of senescent cells in various tissues. Plasma levels of these proteins have been associated with increased mortality and poorer physical function. The associations of them with the incidence of major age-related conditions including heart failure, cardiovascular disease, stroke, and dementia, have not been studied. We measured 35 senescence biomarkers in baseline plasma samples from 1678 participants aged 70–79 years old in the longitudinal Health ABC cohort study. Clinical outcomes were ascertained and validated over an average 11.5 year follow-up. In models adjusted for age, sex, and race, higher levels of most of senescence biomarkers were associated with increased risk of all-cause mortality, mobility limitation, and heart failure. Several were also associated with an increased risk of coronary heart disease, stroke, and dementia. Very few were associated with the risk of cancer. Proteins that were selected by Lasso regression for each outcome that commonly included GDF15 and IL6, significantly improved the prediction of mortality, mobility limitation, and heart failure compared with age, sex, and race alone. These results indicate that levels of senescence biomarkers predict an increased risk of several age-related clinical outcomes and may identify individuals most likely to benefit from senotherapeutics.

Background: Inhibitory effects of denosumab on bone remodeling are reversible and disappear once treatment is discontinued. Herein, we examined whether and to what extent delayed denosumab administration is also associated with fracture risk using nation- wide data. Methods: The study cohort included women aged 45 to 89 years who were started on denosumab for osteoporosis between October 2017 and December 2019 using data from the Korean Health Insurance Review and Assessment service. Participants were stratified according to the time of their subsequent denosumab administration from the last denosumab administration, including those with within 30 days early dosing (ED30), within the planned time of 180-210 days (referent), within 30-90 days of delayed dosing (DD90), within 90-180 days of delayed dosing (DD180), and longer than 181 days of delayed dosing (DD181+). The primary outcome was the incidence of all clinical fractures. Results: A total of 149,199 participants included and 2,323 all clinical fractures (including 1,223 vertebral fractures) occurred. The incidence of all fractures was significantly higher in the DD90 compared to reference group (hazard ratio [HR], 1.2; 95% confidence interval [CI], 1.1 to 1.4). The risk of all fracture was even higher in the longer delayed DD180 group (HR, 1.9; 95% CI, 1.6 to 2.3) and DD181+ group (HR, 1.8; 95% CI, 1.5 to 2.2). Increased risks of fractures with delayed dosing were consistently observed for vertebral fractures. Conclusion: Delayed denosumab dosing, even by 1 to 3 months, was significantly associated with increased fracture risk. Maintaining the correct dosing schedule should be emphasized when starting denosumab.

Greater perceived physical fatigability and lower skeletal muscle energetics are both predictors of mobility decline. Characterizing associations between muscle energetics and perceived fatigability may provide insight into potential targets to prevent mobility decline. We examined associations of in vivo (maximal ATP production, ATPmax) and ex vivo (maximal carbohydrate supported oxidative phosphorylation [max OXPHOS] and maximal fatty acid supported OXPHOS [max FAO OXPHOS]) measures of mitochondrial energetics with two measures of perceived physical fatigability, Pittsburgh Fatigability Scale (PFS, 0–50, higher = greater) and Rating of Perceived Exertion (RPE Fatigability, 6–20, higher = greater) after a slow treadmill walk. Participants from the Study of Muscle, Mobility and Aging (N = 873) were 76.3 ± 5.0 years old, 59.2% women, and 85.3% White. Higher muscle energetics (both in vivo and ex vivo) were associated with lower perceived physical fatigability, all p < 0.03. When stratified by sex, higher ATPmax was associated with lower PFS Physical for men only; higher max OXPHOS and max FAO OXPHOS were associated with lower RPE Fatigability for both sexes. Higher skeletal muscle energetics were associated with 40–55% lower odds of being in the most (PFS ≥ 25, RPE Fatigability ≥ 12) vs least (PFS 0–4, RPE Fatigability 6–7) severe fatigability strata, all p < 0.03. Being a woman was associated with 2–3 times higher odds of being in the most severe fatigability strata when controlling for ATPmax but not the ex vivo measures (p < 0.05). Better mitochondrial energetics were linked to lower fatigability and less severe fatigability in older adults. Findings imply that improving skeletal muscle energetics may mitigate perceived physical fatigability and prolong healthy aging.

Background. Musculoskeletal pain frequently accompanies the development of mobility disability and falls in old age. To better understand this, we aimed to quantify the impact of different pain measures—recalled pain and movement-evoked pain—on 400-meter walk and stair climb time in older adults participating in the Study of Muscle, Mobility and Aging (SOMMA). Methods. In SOMMA (N=879, age=76.3 ± 5.0 years, 59% women, 84% Non-Hispanic White), participants completed usual pace 400m walk (avg=6.6 ± 1.2 min.) and repeat stair climb tests (avg=26.6 ± 7.2 sec.). Assessments of recalled pain included the Brief Pain Inventory short form (BPI-sf), total lower body pain (lower back, hips, knees, feet/ankles), stiffness (hip or knee), and Neuropathy Total Symptom Score (NTSS-6). Movement-evoked pain was assessed separately before and after the 400m walk and repeat stair climb tasks. Multivariable linear regression modeled the associations of pain with time to complete the tasks, reported as β[95%CI] expressed per SD increment of pain measure or β[95%CI] per pain categories, adjusted for age, sex, race, ethnicity, body mass index, prescription medications, and depressive symptoms. Results. Greater degree of any pain measure was associated with longer physical performance time, though intercorrelations between recalled pain measures varied (r=0.13-0.57, p<0.05 for all). For each SD increment in lower body pain, participants had longer walk time (by 10.5 sec [6.1, 14.8]) and stair climb (by 0.6 sec [0.1, 1.1]). Compared to participants with no change in pain upon movement, walk time was longer in those with more pain upon movement (19.5 sec [10.3, 28.7]) (p<0.001) but not those with less pain upon movement; stair climb showed similar patterns. Conclusions. Recalled and movement-evoked pain measures were weakly correlated with one another but similarly associated with time to complete 400m walk and stair climb tests. Different pain assessments capture different functional domains of pain but have similar associations with physical performance in these older adults.