Abstract PURPOSE: Cancer treatments may accelerate biological aging, but longitudinal studies of biological markers of aging are needed to better characterize patterns of biological aging over time. METHODS: We followed 184 women with breast cancer (stage 0-III) from diagnosis to 18 months post treatment. We evaluated biological aging in three treatment groups: chemotherapy (with or without radiotherapy), radiotherapy (without chemotherapy), and neither chemotherapy or radiotherapy. Measures of epigenetic age (PCPhenoAge, GrimAge, DunedinPACE) and telomere length were obtained. Linear mixed models estimated within-group change from pre-treatment to immediate post, 6, 12, and 18 months post-treatment. RESULTS: Women who received chemotherapy exhibited increased epigenetic age in PCPhenoAge, GrimAge, and DunedinPACE and shortening of telomere length acutely following treatment (Ps<0.001). The change attenuated but remained significantly different than baseline for GrimAge, DunedinPACE, and telomere length out to 18 months. Women treated with radiotherapy exhibited a trend for increases in PCPhenoAge and significant telomere length shortening 6 months following treatment that remained modified at 18 months (Ps<0.05). There were no significant changes in epigenetic age or telomere length among women who did not receive either chemotherapy or radiation. CONCLUSION: We observed an acceleration of epigenetic age, an increase in the pace of aging, and telomere shortening among women receiving treatment for breast cancer. The effect was predominantly amongst women who received chemotherapy with or without radiation, pointing to this treatment regimen having the most damaging effects. These results support the premise that cancer treatment may accelerate aging and support further research to identify key clinical and biological targets to remediate these effects. Citation Format: Judith E. Carroll, Cynthia Kusters, Catherine M. Crespi, Michael R. Irwin, Patricia A. Ganz, Laura Petersen, Julienne E. Bower. Longitudinal change in epigenetic aging and telomere length in breast cancer survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2462.

BACKGROUND:Older breast cancer survivors are susceptible to cancer- and treatment-related losses in physical function that can negatively affect daily living activities, mobility, and independence. Although physical activity can improve physical function, few studies have focused on older survivors or explored interrelationships between physical activity and physical function. Longitudinal bidirectional relationships between physical activity and physical function in breast cancer survivors and noncancer controls aged 60+ years were evaluated. METHODS:Survivors (aged 67 ± 7 years; n = 357) newly diagnosed with nonmetastatic breast cancer (stages 0-III) and noncancer controls (aged 67 ± 9 years; n = 254) were assessed at baseline (postsurgery and pre-systemic therapy among survivors) and annual visits for up to 36 months. Physical activity (steps per day) was assessed via actigraphy. The Timed Up and Go test (longer time indicates lower function) and 12-item Short Form Health Survey Physical Component Score evaluated physical function. Data were analyzed via random-intercepts cross-lagged panel models, with controlling for covariates; p values of ˂.05 were considered statistically significant. RESULTS:Starting from the 12-month visit, higher daily steps predicted better subsequent Timed Up and Go time among survivors and controls, and the magnitude of effect was stronger for survivors than controls at 24 months (post hoc comparison, p = .036; survivors: β = -0.420; p = .003; controls: β = -0.211; p = .032). Timed Up and Go time did not predict later daily steps. Associations between steps and the Physical Component Score showed similar patterns. CONCLUSIONS:Higher daily steps predicted better subsequent physical function, especially in survivors. These results highlight the importance of promoting physical activity during cancer survivorship care to maintain functional independence.

Abstract Introduction: Chronic social stressors contribute to disparities in population morbidity and mortality. One putative mechanism for these patterns is that stressors, which are differentially experienced by population sub-groups, result in cumulative wear and tear that increases biological aging via sustained release of stress hormones. However, these relationships have not been well studied in cancer survivors. Methods: This cross-sectional study included 258 Black women from the Detroit Research on Cancer Survivors study. Survivors were 12-60 months post-diagnosis of stage 1-3 breast cancer and had germline DNA available for methylation analyses. Biological age was assessed using the Illumina Infinium Methylation EPIC Array for GrimAge, PhenoAge, Extrinsic Age and Dunedin Pace of Aging. Social stressors included life stress (financial, housing and food insecurity, lack of transportation to medical care, area safety; 0-5 composite score), racial discrimination and neighborhood area deprivation. The outcome was a deficit accumulation frailty index score (0-1; <0.20=robust, 0.20-0.35=pre-frail and >0.35=frail; differences of 0.02-0.06 points are clinically meaningful). Separate linear regression models tested associations of each stressor and deficit accumulation, considering age, time from diagnosis and cytotoxic treatment (chemotherapy, radiotherapy). Mediation models explored whether the relationships between stressors and deficit accumulation were statistically mediated by biological age. Results: Survivors were an average of 58.8 years (range 30-83), were 21.1 (SD 14.6) months from diagnosis and 69.6% were pre-frail or frail. Between 55-78% had biological age greater than chronological age on one or more epigenetic clock and 88% had a faster pace of aging than expected based on chronological age. For each 1-point increase in life stress there was a 0.06 point increase in adjusted deficit accumulation (p<0.001) and life stress accounted for 67% of the explained variance in deficit accumulation. Biological age measured by GrimAge mediated 11.8% of the association between life stress and deficit accumulation (p<0.05) and there was similar but non-significant mediation by other epigenetic measures. Living in the most vs. least deprived area was also associated a large clinically meaningful increase in adjusted deficit accumulation (p=0.007), but discrimination had a smaller, non-significant effect. Conclusions: These findings demonstrate an association between experiencing social stressors and deficit accumulation frailty among Black breast cancer survivors and this association was partially driven by biological aging. Future studies are needed to identify aging pathways and possible modifiable factors that could be targeted by policy, behavioral and pharmacological interventions to reduce disparities and improve outcomes among cancer survivors. Citation Format: Jeanne S. Mandelblatt, Iwalola Awoyinka, Jamaica R. Robinson, Xingtao Zhou, Julie Ruterbusch, Jaeil Ahn, Lucile L. Adams-Campbell, Steven Cole, Ann G. Schwartz, Brent Small, Zhaoming Wang, Kelly Rentscher, Judith E. Carroll. Chronic stressors, biological age and deficit accumulation frailty in black breast cancer survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 866.

BACKGROUND:Insomnia in later life has been associated with accelerated biological ageing; however, little is known about the effects of insomnia treatment on it. In this study, we evaluated the effects of cognitive behavioural therapy for insomnia (CBT-I), compared with sleep education therapy (SET), an active comparator condition, on epigenetic indicators of biological ageing in older adults with insomnia. METHODS:This secondary analysis was conducted within a larger single-site, investigator-initiated randomised controlled trial (ClinicalTrials.govNCT01641263) of adults aged 60 years or older meeting DSM-IV criteria for insomnia disorder recruited from the Los Angeles, CA, USA. Participants in the parent study were randomly assigned to CBI-T or SET according to a computer-generated random number sequence with block sizes ranging from 5-10. Analyses included participants with complete paired epigenetic data. Peripheral blood mononuclear cells were collected before treatment initiation (baseline) and at a follow-up visit occurring at 20-39 months after baseline. Follow-up times exceeding 30 months were winsorised to 30 months. Biological age was measured by use of DNA methylation-derived epigenetic clocks; Dunedin pace of ageing (DunedinPACE), GrimAge, and the principal component version of PhenoAge (PCPhenoAge). FINDINGS:Recruitment for the parent trial was conducted between July 1, 2012, and April 30, 2015. Participants from the CBT-I (n=47; mean age=69·5 [SD 7·0] years) and SET (n=45; mean age=69·4 [5·1] years) groups were randomly selected based on sample availability. Participants receiving CBT-I in the current analysis were more likely to have full remission following treatment than those receiving SET (34% [16 of 47] vs 13% [six of 45]). Compared with those receiving SET, older adults receiving CBT-I showed a significantly slower pace of biological ageing, as estimated by DunedinPACE (-0·02, 95% CI -0·04 to -0·01, false discovery rate [FDR]-adjusted p=0·03). No statistically significant differences were observed for GrimAge (-0·33, -0·68 to 0·03, FDR-adjusted p=0·11) and PCPhenoAge (-0·49, -1·34 to 0·36, FDR-adjusted p=0·26). INTERPRETATION:These findings indicate that a cognitive behavioural intervention for insomnia might slow the pace of biological ageing, as estimated using DunedinPACE. Treatment of insomnia in older adults could therefore represent a strategy for slowing biological ageing in this clinically vulnerable population. FUNDING:National Institute on Aging.

BACKGROUND:Neural substrates of cancer-related cognitive impairment (CRCI) remain poorly understood, especially in older adults facing aging-related cognitive decline and comorbid chronic conditions. METHODS:Breast cancer survivors aged ≥60 years (n = 64) and non-cancer controls (n = 62) completed structural MRI and neuropsychological testing and self-reported cognition and health information at pretreatment baseline and 12- and 24-month follow-ups. Regional gray matter volume and brain age were evaluated using FreeSurfer and brainageR. Longitudinal linear mixed models tested effects of group, time, and group-by-time interactions on volume. Secondary analyses examined relationships between group, comorbidities, age, gray matter volume, and cognition. RESULTS:Survivors exhibited frontal (p = 0.025, q = 0.058), thalamic (p = 0.008, q = 0.052), and limbic (p = 0.015, q = 0.052) gray matter decline relative to controls over 24 months, with smaller effects in parietal (p = 0.055, q = 0.097) and temporal (p = 0.091, q = 0.127) regions. Survivors showed average yearly frontal and thalamic volume loss at twice the rate of controls (p < 0.05). Survivors with a high comorbidity burden (≥3 comorbidities) exhibited the lowest frontal gray matter volume at all timepoints. A trend-level group-by-time interaction for brain age (p = 0.093) suggested accelerated brain aging in survivors. Survivors failed to show practice effects in the attention, processing speed, and executive functioning neuropsychological domain, whereas controls improved significantly over time (group-by-time interaction p = 0.030). CONCLUSIONS:Older breast cancer survivors tended to demonstrate gray matter decline and accelerated brain aging throughout the first two years of survivorship, with comorbidity burden amplifying frontal vulnerability. Findings highlight the need for longitudinal cognitive monitoring and targeted intervention, particularly for older survivors with high comorbidity burden.

BACKGROUND:Early-life adversity (ELA) is linked to adverse mental and physical health across the lifespan. Mitochondrial function is one key, but understudied, mechanism that may be relevant for understanding how ELA becomes biologically embedded. Mitochondria are targets of stress response and mediate stress-related pathology, and impaired mitochondrial function is associated with adverse mental and physical health. However, little clinical research has examined ELA and mitochondrial function. We investigated associations of ELA, operationalized by 2 prominent conceptual models (cumulative risk and threat-deprivation dimensions), with mitochondrial function metrics in a community-based sample of trauma-exposed adults. METHODS:Participants (N = 143, 55.9% female) reported on ELA experiences, and the information was used to create composites for cumulative ELA and threat- and deprivation-related dimensions. Indices of mitochondrial bioenergetics (oxygen consumption rate, extracellular acidification rate) of live peripheral blood mononuclear cells were assessed with the Agilent Seahorse X96 Extracellular Flux Analyzer. Generalized estimating equations were used to examine associations between cumulative ELA and threat- and deprivation-related dimensions with mitochondrial bioenergetic parameters, adjusting for demographic and technical variables. RESULTS:Greater cumulative ELA was associated with lower proton leak and ATP (adenosine triphosphate) production rate from glycolysis and greater maximal respiration and reserve capacity. Dimensional analyses revealed unique and nuanced associations between threat- and deprivation-related ELA and mitochondrial parameters. CONCLUSIONS:This is the first study to examine cumulative risk and dimensional models of ELA in relation to mitochondrial function. We shed light on distinct impacts of cumulative ELA and threat- and deprivation-related experiences, highlighting an overall pattern of greater respiratory capacity associated with ELA.

BACKGROUND:Neighborhood characteristics can affect aging and health. We tested the effects of neighborhood deprivation on deficit accumulation frailty scores in a prospective cohort of breast cancer survivors vs control individuals aged 60 to 98 years. METHODS:Newly diagnosed, nonmetastatic breast cancer survivors (n = 477) and frequency-matched control individuals (n = 434) were enrolled between 2010 and 2023, with up to 5-year follow-up through 2024. Deficit accumulation was measured using a 48-item index (scores of 0-1); a clinically meaningful deficit increase was defined by a 0.06 score increase. Neighborhood deprivation was assessed using the Area Deprivation Index (ADI) at enrollment census block group and categorized into tertiles. Cause-specific Cox models tested the association between ADI and risk of deficit accumulation increase. RESULTS:Participants living in more deprived areas (second and third tertiles of ADI) had a higher risk of increased deficit accumulation (adjusted hazard ratios = 1.38, 95% CI =  1.01 to 1.89, P = .04 and 1.46, 95% CI = 1.07 to 1.94, P = .01 vs first tertile, respectively). Independent of ADI, being a survivor (vs a control individual) was associated with greater risk of increased deficit accumulation (adjusted hazard ratio = 1.69, 95% CI = 1.32 to 2.17, P < .001). Patterns of cumulative incidence rates of increased deficit accumulation differed by ADI: Survivors treated with chemotherapy (with or without hormone therapy) living in more vs less deprived areas had a 20% higher incidence of increased deficit accumulation within 1 year (P = .004), while survivors receiving hormone therapy alone and noncancer control individuals had their most pronounced differences by 4 years (10%, P = .32 and 10%, P = .05, respectively). CONCLUSIONS:Neighborhood deprivation may increase deficit accumulation, with an apparent acceleration of effects among older (≥60 years of age) breast cancer survivors treated with chemotherapy.

Abstract Background: Chemotherapy improves breast cancer survival, but also increases the accumulation of senescent cells in breast cancer survivors. Excess accumulation of senescent cells increases inflammation and tissue damage, which leads to premature onset of age-related diseases (biological age acceleration) in breast cancer survivors. Objective: We integrate a systems biology model of accumulation of senescent cells with chronological age and a well-established Cancer Intervention and Surveillance Modeling Network (CISNET) breast cancer simulation model to estimate the impact of biological age acceleration on survivorship outcomes. Methods: We used published data on senescence biomarker expression level (p16INK4a mRNA expression) in chemotherapy recipient breast cancer survivors to simulate the elevated senescence expression level in the remaining lifetime of breast cancer survivors. The difference in the senescence expression level in the chemotherapy group was evaluated against the expression level in the general female population to quantify the biological age acceleration after chemotherapy. The biological age, instead of chronological age, was used to determine the hazard of non-breast cancer mortality in chemotherapy recipient breast cancer survivors. We used CISNET breast cancer simulation model to simulate multi-birth cohorts of US females diagnosed with breast cancer to estimate survivorship outcomes after chemotherapy. Outcomes included remaining life years after breast cancer diagnosis, absolute number of non-breast cancer deaths, and time-point of transition to dominant risk of non-breast cancer mortality. Results: Biological age acceleration after anthracycline-based regimens caused a greater loss of life years than anthracycline-free regimens for women diagnosed at ages 30-39 years (median of 17.7 years vs. 2.8 years lost). Within the anthracycline group, life years lost varies from 10.4 years to 23.3 years, depending on the level of biological age acceleration. The loss in life years diminished with increasing age at diagnosis (median of 7.5 years vs. 2.2 years lost for 70-79 year old women). The risk of non-breast cancer mortality exceeded breast cancer mortality up to 10-15 years earlier than expected based on chronological age, especially after anthracycline-based regimens. Conclusions: Including biological age acceleration as a factor in breast cancer life history simulation models can help to identify subgroups of breast cancer survivors who need targeted survivorship care for non-breast cancer mortality. Biological age acceleration is a crucial factor especially for the long-term care of younger chemotherapy recipient breast cancer survivors. Citation Format: Swarnavo Sarkar, Mina S. Sedrak, Judith E. Carroll, Clyde Schechter, Hyman B. Muss, Jeanne S. Mandelblatt. Impact of biological aging due to chemotherapy on breast cancer survivorship [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6302.

This study examined how aging-related deficit burden relates to cancer-specific outcomes in men diagnosed at markedly different developmental periods and with different cancer experiences. A modified Deficit Accumulation Index (DAI), a multi-system measure of aging based on proportional health deficits, was computed in two cohorts. Study 1 used cross-sectional data from 171 young adult testicular cancer survivors (ages 18-29). Study 2 used longitudinal data from 114 men with localized prostate cancer (ages 51-81) assessed before treatment and six months post-treatment. In Study 1, DAI scores ranged from 0 to .73 (M = .23), with 47.7% of young adult participants exhibiting medium or high deficit burden. Higher DAI was associated with greater job problems, family disruption, sexual problems, and treatment side effects after adjusting for age and time since diagnosis (p's < .001). In Study 2, DAI scores ranged from 0 to .55 (M = .18), with 34.0% exhibiting medium or high deficit burden. Baseline DAI predicted worsening in hormonal functioning six months after treatment. Greater DAI was also associated with higher circulating interleukin-6 prior to treatment (p < .01). Across both cohorts, deficit accumulation functioned as a marker of survivorship burden; however, the specific outcomes associated with higher deficit burden differed across cohorts. Findings demonstrate the utility of the DAI as a multi-system metric for understanding vulnerability in cancer survivorship.

Abstract Introduction: Deficit accumulation is an important construct in oncology, associated with chemotherapy toxicity, cognitive decline, quality of life, and survival. However, longitudinal patterns of deficit accumulation among cancer survivors remain poorly characterized, and the influence of social health on these trajectories is even less understood. We examined long-term deficit accumulation trajectories in older breast cancer survivors compared with non-cancer controls and evaluated the role of social health in predicting these trajectory memberships. Methods: We included 380 breast cancer survivors and 359 frequency-matched controls enrolled from 2010-2022, each with at least three annual follow-ups through 2024. Social health measures included emotional and tangible support using the Medical Outcomes Study Social Support (MOS-SS) tool, social and family well-being using the Functional Assessment of Cancer Therapy-General (FACT-G) subdomain, and social network size (number of close friends/relatives; categorized as >3 vs. ≤3). Deficit accumulation was assessed at each visit using a 46-item index. Group-based trajectory modeling identified distinct deficit accumulation patterns, and multinomial logistic regression examined predictors of trajectory membership. Results: Three trajectories were identified: 204 rapid decliners (28%; 5-year increase 0.06 [0.012/year], p<10-5), 362 slow decliners (49%; 0.005 increase [0.001/year], p=0.3), and 173 non-decliners (23%; 0.005 decrease [-0.001/year], p=0.4). Breast cancer survivors were more likely to follow a rapid-declining trajectory than non-cancer controls. Among survivors, those who received chemotherapy were most likely to experience rapid deficit accumulation, suggesting persistent treatment-related vulnerability. Higher emotional support predicted lower odds of declining trajectories: each 10-point increase in emotional social support was associated with a 14% lower probability of being a slow decliner (aOR 0.86 [0.74-1.01]) and a 23% lower probability of being a rapid decliner (aOR 0.77 [0.65-0.92]). Higher social and family well-being similarly predicted 15% (aOR 0.85 [0.73-0.99]) and 21% (aOR 0.79 [0.68-0.93]) lower odds of being slow and rapid decliners, respectively. Having more than 3 close friends predicted a 65% lower probability of becoming a rapid decliner (aOR 0.38 [0.17-0.87]). Conclusions: Deficit accumulation trajectories in older women are heterogeneous, and breast cancer diagnosis and chemotherapy appear to contribute to more rapid deficit accumulation. Social health—including emotional support, social and family well-being, and larger social networks—emerged as a strong protective factor, slowing the pace of deficit accumulation among both breast cancer survivors and non-cancer controls. Citation Format: Eunji Choi, Iwalola Awoyinka, Jaeil Ahn, Tim A. Ahles, Ashley L. Artese, Traci N. Bethea, Judith E. Carroll, Harvey Jay Cohen, Heather S. Jim, Brenna C. McDonald, Zev Nakamura, Sunita Patel, James C. Root, Andrew J. Saykin, Brent Small, Ying Wang, Wanting Zhai, Jeanne S. Mandelblatt. Social support as a predictor of deficit accumulation in older breast cancer survivors and non-cancer controls [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2465.

Abstract Background: Sleep disturbances, such as insomnia, are common in postmenopausal women and may negatively impact physical functioning. These disturbances are more frequent in breast cancer survivors than in the general female population. Limited data exist on how sleep affects physical function in older breast cancer patients. We analyzed whether sleep quality influences physical function at a one-year follow-up, and vice versa. Methods: Data were from the Thinking and Living with Cancer study, a multicenter, longitudinal study involving women aged 60 and older, newly diagnosed with breast cancer and frequency-matched non-cancer controls. Participants were followed annually for up to five years. Sleep quality was assessed with the PSQI (range 0-21; higher scores indicate poorer sleep quality); physical functioning was measured by the SF-12 physical component score (PCS) and the Timed Up and Go (TUG). A 3-5 point SF-12 PCS decline was considered clinically meaningful. Random intercept cross-lag panel models (RI-CLPM) analyzed associations using data from 767 women (339 controls and 428 survivors), adjusting for age, race, comorbidities, and recruitment site. Results: Mean age of participants was 69.5 years (70.0 in survivors vs. 69.3 in controls). Disrupted sleep was more common among survivors at baseline (PSQI above 5: 43.9% vs. 29.0%; p less than 0.001) and remained more prevalent during follow-up. Survivors showed a clinically meaningful decline in PCS (-2.8 points in year 1; -3.0 points over two years), whereas controls had a small, gradual, non-clinically meaningful decline (≈ -0.5 points/year). There was no clear trajectory for TUG, and the RI-CLPM revealed no significant associations between PSQI and TUG. In survivors, each 1-point higher PSQI predicted 0.4-0.5 points (P less than 0.001) lower SF-12 PCS at the subsequent annual visit during the first three years, decreasing to 0.3 points by year 4 (P = 0.03). Among controls, effects were small initially (-0.25 points, p = 0.10) but from years 2 to 5 a 1-point PSQI increase predicted 0.4-0.65 points lower SF-12 PCS (p = 0.01 to less than 0.001). For both survivors and controls, a 10-point worsening in a woman’s PSQI relative to her usual level would be expected to correspond to about a 4-point lower SF-12 PCS one year later, assuming a 0.4-point decrease in PCS per 1-point increase in PSQI. Conclusion: Sleep disruption is associated with subsequent declines in physical function among survivors and controls, which can reach clinically meaningful magnitudes as sleep quality worsens. Given the high prevalence of sleep problems among breast cancer survivors, routine monitoring for sleep disturbances and timely intervention may help preserve function in the growing population of older cancer survivors, particularly in the early years following treatment. This work was conducted with contributions from the entire TLC-Age research team. Citation Format: Cynthia Kusters, Wanting Zhai, Xingtao Zhou, Zev Nakamura, Jaeil Ahn, Ashley L. Artese, Deena Graham, Chloe Casagrande, Kathleen van Dyk, Tim A. Ahles, Traci N. Bethea, Harvey Cohen, Claudine Isaacs, Heather S. Jim, Brenna McDonald, Sunita Patel, James C. Root, Andrew Saykin, Brent Small, Jeanne S. Mandelblatt, Judith E. Carroll, TLC-Age Research Group.. The association between sleep and physical function in the longitudinal TLC cohort study of women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2466.

Cognitive effects of breast cancer antiestrogen endocrine therapy are a salient concern for survivors, given the growing evidence that estrogen plays a role in late-life dementia risk. The APOE4 genotype has been linked with risk for cognitive difficulties, studied mainly in younger cancer survivors. We found that women aged 60+ with nonmetastatic breast cancer enrolled in the prospective Thinking and Living with Cancer study who underwent endocrine therapy had lower subjective (P = .06) and objective (P = .08) cognitive function than frequency-matched controls across time. At 5 years, however, women with breast cancer exposed to endocrine therapy and APOE4 carriers in particular exhibited lower learning and memory scores than other groups (P < .05). Our results suggest endocrine therapy may have long-term effects on cognitive function in women with breast cancer, particularly APOE4 carriers. Further characterization of genetic risk for long-term cognitive decline will be useful to inform survivorship care of older women.

BACKGROUND:Autism is a lifelong neurodevelopmental condition, yet aging trajectories in autistic adults remain poorly understood. We conducted a systematic review of studies examining age-related cognitive, neural, and physical health outcomes in autistic adults to clarify emerging patterns and identify priority areas for future research. METHODS:A systematic search of PubMed, PsycINFO, and Web of Science identified 56 eligible studies that included autistic adults and provided either longitudinal data or explicit age-by-diagnosis comparisons. Findings were synthesized separately by domain. RESULTS:Current evidence does not support globally accelerated or attenuated aging in autism. Most objective cognitive measures showed comparable age-related patterns across autistic and non-autistic adults, although subjective cognitive complaints were consistently elevated. Neuroimaging findings were similarly mixed. Most studies reported no structural or functional differences, though some found evidence of vulnerability in white matter microstructure. Physical health studies more consistently identified elevated rates of neurodegenerative diseases, sensory impairments, and musculoskeletal conditions, but comparable or lower rates for cancer. Cardiovascular findings were complex, with lower hypertension rates but higher rates of severe outcomes such as heart failure and stroke, suggesting gaps in early detection and preventive care. CONCLUSION:Rather than generalized accelerated aging, findings point toward targeted vulnerabilities in autism. Subjective cognitive complaints, white matter integrity, and elevated neurodegeneration rates represent the clearest targets for future surveillance. Critically, existing research almost exclusively involves autistic adults without intellectual disability, limiting generalizability. Advancing the field requires longitudinal designs, more inclusive samples, and a shift from group-level comparisons toward understanding within-group heterogeneity and individual risk profiles.

OBJECTIVE:Trauma exposure may be linked to accelerated biological aging. However, studies have largely considered childhood abuse, with limited consideration of lifetime trauma exposure, particularly for women. Furthermore, few studies have considered newer epigenetic clocks, which have enhanced links with health outcomes. Among midlife women, we investigated whether lifetime trauma exposure is associated with older epigenetic age with several generations of clocks. We explored associations between childhood maltreatment and epigenetic age and racial differences in associations between trauma and epigenetic age. METHOD:Two hundred sixteen women (Mage = 59 years, 83% non-Hispanic White, 13% Black, and 4% other race/ethnicities) underwent physical measures, questionnaires to assess lifetime trauma exposure, and a blood draw. A subset of 123 women completed childhood maltreatment measures. Extrinsic epigenetic age, GrimAge, principal component-based PhenoAge, and DunedinPACE were calculated. Clocks were residualized for age and Z-scored for analysis. Associations between trauma and epigenetic age were estimated in linear regression (covariates race, education, body mass index, and estimated cell counts). Interactions by race were tested. RESULTS:Relative to women without trauma exposure, those with ≥ 2 lifetime traumas had older epigenetic age, GrimAge, 1: B (SE) = 0.15 (0.15), p = .31, 2+: B (SE) = 0.39 (0.13), p = .004; DunedinPACE, 1: B (SE) = 0.23 (0.12), p = .07, 2+: B (SE) = 0.33 (0.11), p = .003. Childhood sexual abuse was also associated with older epigenetic age, GrimAge: B (SE) = 0.56 (0.24), p = .021. Exploratory models suggested that trauma was related to epigenetic age primarily among Black women. CONCLUSION:Among midlife women, greater lifetime trauma and possibly childhood sexual abuse were associated with older epigenetic age, independent of chronologic age. Black women may be particularly affected. (PsycInfo Database Record (c) 2025 APA, all rights reserved).

Adverse experiences over the lifespan can increase risk for poor health outcomes, likely operating in part through accelerated biological aging. From a life course perspective, the extent to which adverse experiences in adulthood predict biological aging will vary as a function of early life adversity, yet few studies have tested this. In this cross-sectional, pre-registered study, we examined associations of early life adversity and past-year potentially traumatic events and their interaction with telomere length in a sample of racially and ethnically diverse and predominantly low-income women (n = 127). We also tested hair cortisol as a potential pathway linking early life adversity and potentially traumatic events with telomere length. Women reported on experiences of early life adversity and the number and negative impact of past-year potentially traumatic events during interviews. Buccal cells and hair samples were collected to assess telomere length and cortisol, respectively. More negative impact of past-year potentially traumatic events was associated with shorter telomere length. However, the strength of this association was conditional on early life adversity and strongest at lower levels of early life adversity. Both greater early life adversity and more negative impact of potentially traumatic events were associated with higher hair cortisol, but hair cortisol was not associated with telomere length. Results suggest that early life adversity modifies the association between subsequent trauma and telomere length and advances understanding of how lifespan adversity shapes biological aging. These findings may inform future research to examine dynamic biological processes linking lifespan adverse experiences to health using longitudinal designs.

Psychosocial stress and adversity have been linked to accelerated aging and increased risk for age-related diseases. Animal and in vitro studies have shown that exposure to stress hormones (catecholamines, glucocorticoids) can impact biological aging processes such as DNA damage and cellular senescence, suggesting they play a key role in links between stress and aging; however, these associations have not been well investigated in humans. We examined cross-sectional associations between chronic stress exposures, stress hormones, and biological aging markers in midlife adults and whether stress hormones mediated associations between stress and aging. Participants were 531 adults aged 26-78 years (Mage = 53.9, 50.1% female) in the nationally representative Midlife in the United States Refresher cohort. They reported chronic stress exposures in childhood and adulthood (Stressful Life Event Inventory) and provided 12-hour urine samples used to assess norepinephrine, epinephrine, and cortisol. RNA sequencing of peripheral blood mononuclear cells derived aging biomarkers: the DNA damage response (DDR; 30-gene composite), cellular senescence signal p16INK4a (CDKN2A), and the pro-inflammatory senescence-associated secretory phenotype (SASP; 57-gene composite). Regression models adjusting for age, sex, race/ethnicity, BMI, smoking status, alcohol use, and medications revealed that more childhood exposures were associated with higher norepinephrine (beta = 0.09, p = 0.04), independent from adult exposures. Higher norepinephrine was associated with elevated DDR expression (beta = 0.17, p < 0.001). Higher norepinephrine (beta = 0.14, p = 0.003) and epinephrine (beta = 0.10, p = 0.02) were both associated with elevated SASP expression. Statistical mediation analyses implicated elevated norepinephrine as a plausible mediator of associations between childhood exposures and both DDR (unstandardized b = 0.005, 95% CI [0.0002, 0.011]) and SASP (b = 0.002, 95% CI [0.0001, 0.05]). Findings provide preliminary evidence in humans that stress hormones may impact key biological aging processes and may be a mechanism linking chronic stress exposures in childhood to accelerated aging later in life.

The central premise of this article is that a portion of the established relationships between social determinants of health and racial and ethnic disparities in cancer morbidity and mortality is mediated through differences in rates of biological aging processes. We further posit that using knowledge about aging could enable discovery and testing of new mechanism-based pharmaceutical and behavioral interventions ("gerotherapeutics") to differentially improve the health of cancer survivors from minority populations and reduce cancer disparities. These hypotheses are based on evidence that lifelong differences in adverse social determinants of health contribute to disparities in rates of biological aging ("social determinants of aging"), with individuals from minoritized groups experiencing accelerated aging (ie, a steeper slope or trajectory of biological aging over time relative to chronological age) more often than individuals from nonminoritized groups. Acceleration of biological aging can increase the risk, age of onset, aggressiveness, and stage of many adult cancers. There are also documented negative feedback loops whereby the cellular damage caused by cancer and its therapies act as drivers of additional biological aging. Together, these dynamic intersectional forces can contribute to differences in cancer outcomes between survivors from minoritized vs nonminoritized populations. We highlight key targetable biological aging mechanisms with potential applications to reducing cancer disparities and discuss methodological considerations for preclinical and clinical testing of the impact of gerotherapeutics on cancer outcomes in minoritized populations. Ultimately, the promise of reducing cancer disparities will require broad societal policy changes that address the structural causes of accelerated biological aging and ensure equitable access to all new cancer control paradigms.