Epigenetic Age Acceleration and Hearing: Observations From the Baltimore Longitudinal Study of Aging

Objectives: Age-related hearing loss (ARHL) is highly prevalent among older adults, but the potential mechanisms and predictive markers for ARHL are lacking. Epigenetic age acceleration has been shown to be predictive of many age-associated diseases and mortality. However, the association between epigenetic age acceleration and hearing remains unknown. Our study aims to investigate the relationship between epigenetic age acceleration and audiometric hearing in the Baltimore Longitudinal Study of Aging (BLSA).Methods: Participants with both DNA methylation and audiometric hearing measurements were included. The main independent variables are epigenetic age acceleration measures, including intrinsic epigenetic age acceleration—“IEAA,” Hannum age acceleration—“AgeAccelerationResidualHannum,” PhenoAge acceleration—“AgeAccelPheno,” GrimAge acceleration—“AgeAccelGrim,” and methylation-based pace of aging estimation—“DunedinPoAm.” The main dependent variable is speech-frequency pure tone average. Linear regression was used to assess the association between epigenetic age acceleration and hearing.Results: Among the 236 participants (52.5% female), after adjusting for age, sex, race, time difference between measurements, cardiovascular factors, and smoking history, the effect sizes were 0.11 995% CI: (–0.00, 0.23), p = 0.054] for Hannum’s clock, 0.08 [95% CI: (–0.03, 0.19), p = 0.143] for Horvath’s clock, 0.10 [95% CI: (–0.01, 0.21), p = 0.089] for PhenoAge, 0.20 [95% CI: (0.06, 0.33), p = 0.004] for GrimAge, and 0.21 [95% CI: (0.09, 0.33), p = 0.001] for DunedinPoAm.Discussion: The present study suggests that some epigenetic age acceleration measurements are associated with hearing. Future research is needed to study the potential subclinical cardiovascular causes of hearing and to investigate the longitudinal relationship between DNA methylation and hearing.

Daily Physical Activity Patterns: A Window on Cognitive Decline in the Baltimore Longitudinal Study of Aging (BLSA)

Gradual disengagement from essential daily physical activity (PA) necessary for independent living could signal present or emerging mild cognitive impairment (MCI) or Alzheimer’s disease (AD). We used BLSA data to examine whether PA patterns including: 1) total activity counts/day, 2) minutes/day spent active, and 3) activity fragmentation (reciprocal of the mean active bout length) differs between participants with adjudicated normal cognition (n=498) and MCI/AD diagnoses (n=32). Linear models were used and adjusted for demographics, APOE-e4 status, morbidity, and gait speed. Compared to those with normal cognition, those with MCI/AD had 3.0% higher activity fragmentation (SE=1.1%, p=0.006) but similar mean total activity counts/day (p=0.08) and minutes/day spent active (p=0.19). Results suggest that activity fragmentation may arise as a compensatory strategy in the absence of reduced activity in MCI and early AD and that activity monitoring may be potentially useful for detecting MCI and AD at an earlier stage.

Associations Between Perceived Fatigability and Amyloid Status in the Baltimore Longitudinal Study of Aging

Higher level of and greater longitudinal increase in perceived fatigability are linked to cognitive decline and lower brain volumes in older adults. However, it remains unclear whether perceived fatigability is associated with Alzheimer’s disease-related brain pathology. In the BLSA, 163 participants without neurological disease or cognitive impairment (aged 74.7+/-8.4 years, 45% men) were assessed for perceived fatigability using rating of perceived exertion after a 5-minute (0.67 m/s) treadmill walk and Aß burden using 11C-Pittsburgh compound B (PiB) positron emission tomography. Forty-four participants were PiB+ based on a mean cortical distribution volume ratio (DVR) cut point of 1.066. After adjusting for demographics, body composition, comorbidities and ApoE-e4, higher perceived fatigability was not associated with PiB+ status (OR=0.84; 95% CI: 0.69, 1.05). Results suggest perceived fatigability may contribute to cognitive decline through pathways other than Aß pathology. Future studies should target other mechanisms linking perceived fatigability and cognitive decline.

Association of Hearing Impairment With Higher Level Physical Functioning and Walking Endurance

The longitudinal associations between hearing impairment and higher-level functional measures and the potential confounding role of vestibular function have not been assessed. We investigated these associations in 831 participants of the Baltimore Longitudinal Study of Aging (2012–2019). Hearing was measured using pure-tone audiometry and categorized using WHO standards. Physical function was assessed with the Health Aging and Body Composition Physical Performance Battery (HABCPPB, higher=better) and walking endurance with time to walk 400 meters. Multivariable regression models tested the hypotheses that participants with hearing impairment have poorer physical outomes. In a subset, we further adjusted for vestibular function. Hearing impairment was associated with decrements in higher-level physical performance and walking endurance, and faster decline over time, regardless of vestibular function. Among participants with any hearing impairment, hearing aid users were faster in the 400-m walk. Early screening for higher-level functional loss among older adults with hearing loss is warranted.

Fatigability: An Early Marker of Diminished Renal Function?

Renal function declines markedly with age due to normal aging and/or disease processes and impacts multiple systems. Diminished renal function may manifest as low exercise tolerance and fatigue threshold. Using data on 951 well-functioning (usual gait speed >.67m/s and no difficulty walking ¼ mile) men and women (51%) aged 60-89 years in the Baltimore Longitudinal Study of Aging, we evaluated the cross-sectional association between perceived fatigability (Rating Perceived Exertion after 5-minute treadmill walk at 1.5mph) categorized as 6-7, 8-9, 10-11 and 12+ and GFR using Cockcroft-Gault. For each fatigability increment, likelihood of suboptimal (GFR=75-89, 21%), diminished (GFR=60-74, 26%) and poor renal function (GFR=15-59, 30%) relative to GFR≥90 was respectively OR(95%CI)p-value 1.51(1.16-1.96).002, 1.38(1.04-1.83).027 and 1.68(1.22-2.31).002 adjusted for demographics, weight, height, smoking, exercise and anemia. Findings were similar for men and women. Perceived fatigability may facilitate identification of apparently well-functioning older adults on the precipice of suboptimal to poor renal function.

Links of Sleep Duration with Biomarkers of Accelerated Aging: the Baltimore Longitudinal Study of Aging

Sleep disorders and sleep deprivation have been linked to markers of biological aging, including methylation change and increases in white blood cell and neutrophil counts. However, little is known regarding the association of sleep duration with biological markers of aging. We investigated links of self-reported sleep duration with biological aging markers in 615 participants in the Baltimore Longitudinal Study of Aging (BLSA) aged ≥50 years (mean = 71.0 ± 11.2, 49.6% women, 68.8% white) with data on self-reported sleep duration in hours (i.e., ≤6 (n=131), >6 to 7 (n=234), >7 (n=250)), demographics, and genetic and methylation data (mDNA). Our aging biomarker outcomes were four epigenetic clocks (Horvath, Hannum, PhenoAge, and GrimAge), mDNA-estimated PAI1, and estimated granulocyte count. After adjustment for age, sex, and race, compared to those sleeping ≤6 hours, those reporting >7 hours of sleep had faster biological aging according to Hannum age-acceleration, PhenoAge, GrimAge, mDNA-estimated PAI1, and granulocyte count. In addition, sleep duration interacted with age, such that compared to individuals reporting ≤6 hours of sleep, individuals reporting >6 to 7 hours showed lower GrimAge with increasing age, and with sex, such that males with longer sleep duration (>6 to 7 and >7 hours) showed a lower granulocyte count compared to females. Findings suggest that both short and long sleep duration are associated with and may contribute to accelerated aging. Prospective studies in larger samples are needed to examine whether changes in sleep duration precede changes in aging biomarkers.

Association Between Arterial Stiffness and Fatigability in Well-Functioning Older Adults

The association between vascular health measured by arterial stiffness and fatigability, a marker of future mobility decline, is unknown. We examined 1210 men (47.7%) and women from the Baltimore Longitudinal Study of Aging, mean age 66.6 ± 13.9 years. Perceived fatigability was assessed after a 5-minute, treadmill walk using Borg rating (range 6-20). Arterial stiffness was determined by carotid femoral pulse wave velocity (PWV). In linear regression analyses fatigability and PWV were associated in men (Beta/P-value) (0.160/0.001) and women (0.136/0.008). Adjustment for mean arterial and pulse pressure attenuated the association in women (0.104/0.050) but not men (0.160/0.001). The association was significant among those with slower usual and rapid gait speeds, longer 400m walk time and slower repeated chair stands pace (all p<0.05). Arterial stiffness is associated with a greater proneness to fatigue especially in older adults exhibiting poorer mobility. The underlying mechanisms appear to differ between men and women.

Cognition Moderates the Relationship Between Hearing and Mobility in Cognitively Normal Older Adults

Recent data has shown a consistent but modest association between hearing impairment and poor mobility; both are strongly associated with cognition. Cognitive function may moderate the relationship between hearing and mobility. We analyzed 601 cognitively normal older participants from the Baltimore Longitudinal Study of Aging who had concurrent data on cognition (attention, executive function, sensorimotor function), hearing (pure-tone average, PTA), and mobility (6-meter gait speed, 400-meter time). We performed multivariable-adjusted linear regression to test two-way interactions between each cognitive measure and PTA. There were significant PTA interactions with all cognitive measures on 400-meter time. There was a significant interaction between PTA and sensorimotor function on 6-meter gait speed. Among cognitively normal older adults, poorer hearing is more strongly associated with poor mobility in those with low cognition, especially sensorimotor function. Future studies are needed to understand how cognition may moderate the relationship of hearing impairment with mobility decline over time.

Circadian Rest and Activity Rhythms and Cognitive Change in the Baltimore Longitudinal Study of Aging

Alterations in 24-hour movement patterns, or circadian rest/activity rhythms (RARs), commonly occur with aging. Using linear mixed effects (LME) modeling, we examined associations of baseline RARs with longitudinal change in cognition. Participants (N=424; 47% male, baseline age 72.8±10.1 years) were from the Baltimore Longitudinal Study of Aging and completed 5.6±0.8 nights of wrist actigraphy at baseline. Tests of memory, executive function, attention, language, and visuospatial ability were administered at baseline and subsequent visits (3.7±1.7 years of follow-up in those with >1 visit (n=295)). In unadjusted random intercept and slope LME models, greater RAR stability predicted slower memory decline, and higher activity during participants’ least active 5 hours (L5) predicted slower decline in visuospatial ability. After covariate adjustment, higher activity in participants’ most active 10 hours (M10) and higher L5 predicted slower decline in visuospatial ability (p<.05). Further research is needed on RARs as risk factors for later-life cognitive decline.