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Gerotherapeutics: Aging Mechanism-based Pharmaceutical and Behavioral Interventions to Reduce Cancer Racial and Ethnic Disparities
Abstract
The central premise of this article is that a portion of the established relationships between social determinants of health and racial/ethnic disparities in cancer morbidity and mortality are 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 minoritized cancer survivors 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 minoritized groups having accelerated aging (ie, a steeper slope or trajectory of biological aging over time relative to chronological age) more often than non-minoritized groups. Acceleration of biological aging can increase the risk, age of onset, aggressivity and/or 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 minoritized vs non-minoritized survivor populations.
We highlight key targetable biological aging mechanisms with potential applications to reducing cancer disparities and discuss methodological considerations for pre-clinical 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.
... The global anti-aging market, valued at over $60 billion, reflects a substantial and increasing demand for products and treatments that target aging [7]. Middle-aged and older adults have historically been the primary consumers of anti-aging products, but recent trends indicate a growing interest from younger demographics seeking preventative measures [8,9]. Shifts in public opinion also reflect a broader acceptance of anti-aging treatments, with many consumers focusing on holistic approaches that integrate skincare, lifestyle adjustments, and emerging therapeutic technologies [9]. ...
... Middle-aged and older adults have historically been the primary consumers of anti-aging products, but recent trends indicate a growing interest from younger demographics seeking preventative measures [8,9]. Shifts in public opinion also reflect a broader acceptance of anti-aging treatments, with many consumers focusing on holistic approaches that integrate skincare, lifestyle adjustments, and emerging therapeutic technologies [9]. ...
Background/Aim
Aging involves a progressive deterioration in physiological functions and increased disease susceptibility, impacting all organs and tissues, especially the skin. Skin aging is driven by intrinsic factors (genetics, cellular metabolism) and extrinsic factors (environment, lifestyle). Understanding these mechanisms is vital for promoting healthy aging and mitigating skin aging effects. This review aims to summarize the key factors influencing skin and intrinsic aging, providing a comprehensive understanding of the underlying mechanisms and contributing elements.
Methods
A comprehensive literature review was conducted, focusing on peer‐reviewed journals, clinical studies, and scientific reviews published within the last two decades. The inclusion criteria prioritized studies that addressed intrinsic and extrinsic mechanisms of skin aging. To ensure the relevance and quality of the selected sources, a systematic approach was used to assess study design, sample size, methodology, and the significance of the findings in the context of skin aging.
Findings
The review identifies major internal factors, such as cellular senescence, genetic predisposition, telomere shortening, oxidative stress, hormonal changes, metabolic processes, and immune system decline, as pivotal contributors to intrinsic aging. External factors, including UV radiation, pollution, lifestyle choices (diet, smoking, alcohol consumption, and sleep patterns), and skincare practices, significantly influence extrinsic skin aging. The interplay between these factors accelerates aging processes, leading to various clinical manifestations like wrinkles, loss of skin elasticity, pigmentation changes, and texture alterations.
Conclusion
A comprehensive understanding of both extrinsic and intrinsic factors contributing to skin aging is essential for developing effective prevention and intervention strategies. The insights gained from this review highlight the importance of a multifaceted approach, incorporating lifestyle modifications, advanced skincare routines, and emerging therapeutic technologies, to mitigate the effects of aging and promote healthier, more resilient skin.
... Historically, middle-aged and older adults were the primary consumers of antiaging products. However, recent trends suggest a growing interest among younger individuals in preventive measures (Mandelblatt and Antoni, 2025). ...
Polygonati Rhizoma has been reported to exhibit the ability to retard skin aging. However, the precise molecular mechanisms underlying remain largely elusive. In this study, we screened 9 active compounds in Polygonati Rhizoma using the TCMSP and SwissADME databases. Subsequently, 285 potential targets were identified via Swiss Target Prediction Database. Concurrently, 800 genes related to skin aging were retrieved from GeneCards, OMIM, and TTD databases. By intersecting these datasets with the potential targets of Polygonati Rhizoma , we pinpointed 17 overlapping genes. These genes were further subjected to GO function annotation and KEGG pathway analysis using DAVID database. A compound-target-pathway network was then constructed using Cytoscape software, highlighting two compounds (4',5-dihydroxyflavone and baicalein) and six targets (MAPK1, MAPK10, MMP9, PTGS2, PDGFRB, and CYP1B1). Molecular docking revealed that the binding energy between 4',5-dihydroxyflavone and baicalein with the six targets was less than -5 kcal/mol, particularly for MMP9, PTGS2, and CYP1B1, indicating a stable interaction. Finally, Polygonati Rhizoma flavonoids were isolated, and their antioxidant capacity was evaluated in vitro, confirming significant antioxidant activity. Collectively, our findings provide a systematic foundation for elucidating the molecular mechanisms underlying the anti-aging effects of Polygonati Rhizoma and offer valuable insights into the development of anti-skin aging cosmetics.
Background
The purpose of this study was to describe the characteristics of the NIH‐funded grant portfolio focused on cancer and accelerated aging.
Methods
Research project grants focused on cancer survivors and aging trajectories that were newly funded during fiscal years 2013 through 2023 were identified by first using a text mining algorithm from the NIH Research, Condition, and Disease Categorization (RCDC) system with cancer survivorship‐relevant terms and then a list of aging‐related terms that included aging, neurocognition, and physical function. Included grants were double coded to extract study characteristics.
Results
A total of 166 grants were identified, with the National Cancer Institute (NCI) and National Institute on Aging (NIA) funding 62.0% and 23.5% of the grants, respectively. The number of newly funded grants rose from nine in 2013 to 27 in 2023. Overall, the majority were observational studies (65.1%); 45% included study samples of multiple cancer types. The most commonly examined outcomes were cognitive (54.4%) or physical (37.5%) functioning; 30% of grants incorporated an aging‐related biomarker. Few grants focused on racial and ethnic minority (3.0%) or rural cancer survivors (2.4%).
Conclusions
This portfolio analysis showed an increase in the number of NIH‐funded grants focused on cancer survivors and accelerated aging, but notable gaps are evident. Given the rapidly growing survivor population, many of whom will experience accelerated aging trajectories, there is a critical need to better understand accelerated aging phenotypes and mechanisms, so that those at the highest risk for adverse aging‐related effects can be identified and interventions developed.
For centuries, aging was considered inevitable and immutable. Geroscience provides the conceptual framework to shift this focus toward a new view that regards aging as an active biological process, and the biological age of an individual as a modifiable entity. Significant steps forward have been made toward the identification of biomarkers for and measures of biological age, yet knowledge gaps in geroscience are still numerous. Animal models of aging are the focus of this perspective, which discusses how experimental design can be optimized to inform and refine the development of translationally relevant measures and biomarkers of biological age. We provide recommendations to the field, including: the design of longitudinal studies in which subjects are deeply phenotyped via repeated multilevel behavioral/social/molecular assays; the need to consider sociobehavioral variables relevant for the species studied; and finally, the importance of assessing age of onset, severity of pathologies, and age-at-death. We highlight approaches to integrate biomarkers and measures of functional impairment using machine learning approaches designed to estimate biological age as well as to predict future health declines and mortality. We expect that advances in animal models of aging will be crucial for the future of translational geroscience but also for the next chapter of medicine.
PURPOSE
Socioeconomic status (SES) influences the survival outcomes of patients with early breast cancer (EBC). However, limited research investigates social inequalities in their quality of life (QoL). This study examines the socioeconomic inequalities in QoL after an EBC diagnosis and their time trends.
PATIENTS AND METHODS
We used data from the French prospective multicentric CANTO cohort (ClinicalTrials.gov identifier: NCT01993498 ), including women with EBC enrolled between 2012 and 2018. QoL was assessed using the European Organisation for Research and Treatment of Cancer QoL Core 30 questionnaire (QLQ-C30). summary score at diagnosis and 1 and 2 years postdiagnosis. We considered three indicators of SES separately: self-reported financial difficulties, household income, and educational level. We first analyzed the trajectories of the QLQ-C30 summary score by SES group. Then, social inequalities in QLQ-C30 summary score and their time trends were quantified using the regression-based slope index of inequality (SII), representing the absolute change in the outcome along socioeconomic gradient extremes. The analyses were adjusted for age at diagnosis, Charlson Comorbidity Index, disease stage, and type of local and systemic treatment.
RESULTS
Among the 5,915 included patients with data on QoL at diagnosis and at the 2-year follow-up, social inequalities in QLQ-C30 summary score at baseline were statistically significant for all SES indicators (SII financial difficulties = –7.6 [–8.9; –6.2], SII income = –4.0 [–5.2; –2.8]), SII education = –1.9 [–3.1; –0.7]). These inequalities significantly increased (interaction P < .05) in year 1 and year 2 postdiagnosis, irrespective of prediagnosis health, tumor characteristics, and treatment. Similar results were observed in subgroups defined by menopausal status and type of adjuvant systemic treatment.
CONCLUSION
The magnitude of preexisting inequalities in QoL increased over time after EBC diagnosis, emphasizing the importance of considering social determinants of health during comprehensive cancer care planning.
Simple Summary
Non-Hispanic Black breast cancer survivors have poorer outcomes than White survivors, but the biological mechanisms underlying these disparities are unclear. We discovered novel race-based differences in systemic DNA damage and repair activity among breast cancer survivors. This finding suggests DNA damage and repair are important basic science mechanisms in cancer disparities.
Abstract
Non-Hispanic Black breast cancer survivors have poorer outcomes and higher mortality rates than White survivors, but systemic biological mechanisms underlying these disparities are unclear. We used circulating leukocytes as a surrogate for measuring systemic mechanisms, which might be different from processes in the target tissue (e.g., breast). We investigated race-based differences in DNA damage and repair, using a novel CometChip assay, in circulating leukocytes from breast cancer survivors who had completed primary cancer therapy and were cancer free. We observed novel race-based differences in systemic DNA damage and repair activity in cancer survivors, but not in cells from healthy volunteers. Basal DNA damage in leukocytes was higher in White survivors, but Black survivors showed a much higher induction after bleomycin treatment. Double-strand break repair activity was also significantly different between the races, with cells from White survivors showing more sustained repair activity compared to Black leukocytes. These results suggest that cancer and cancer therapy might have long-lasting effects on systemic DNA damage and repair mechanisms that differ in White survivors and Black survivors. Findings from our preliminary study in non-cancer cells (circulating leukocytes) suggest systemic effects beyond the target site, with implications for accelerated aging-related cancer survivorship disparities.
Discrimination is a social determinant of health and health disparities for which the biological mechanisms remain poorly understood. This study investigated the hypothesis that discrimination contributes to poor health outcomes by accelerating biological processes of aging. We analyzed survey and blood DNA methylation data from the Midlife in the United States (MIDUS) study (N = 1967). We used linear regression analysis to test associations of everyday, major, and workplace discrimination with biological aging measured by the DunedinPACE, PhenoAge, and GrimAge2 epigenetic clocks. MIDUS participants who reported more discrimination tended to exhibit a faster pace of aging and older biological age as compared to peers who reported less discrimination. Effect-sizes for associations tended to be larger for the DunedinPACE pace-of-aging clock (effect-size range r = 0.1–0.2) as compared with the PhenoAge and GrimAge2 biological-age clocks (effect-sizes r < 0.1) and for experiences of everyday and major discrimination as compared with workplace discrimination. Smoking status and body-mass index accounted for roughly half of observed association between discrimination and biological aging. Reports of discrimination were more strongly associated with accelerated biological aging among White as compared with Black participants, although Black participants reported more discrimination overall and tended to exhibit older biological age and faster biological aging. Findings support the hypothesis that experiences of interpersonal discrimination contribute to accelerated biological aging and suggest that structural and individual-level interventions to reduce discrimination and promote adaptive coping have potential to support healthy aging and build health equity.
The population of cancer survivors has markedly increased due to the rapid improvements in cancer treatment. However, cancer survivors experience accelerated aging, which leads to chronic diseases and other age-related conditions, such as frailty. Those conditions may persist years after cancer diagnosis and treatment. Cellular senescence, a hallmark of aging, is one of the mechanisms that contribute to accelerated aging in cancer survivors. Several aging measures, including measures based on clinical markers and biomarkers, have been proposed to estimate the aging process, and some of them have shown associations with mortality and frailty in cancer survivors. Several anti-aging interventions, including lifestyle changes and anti-aging drugs, have been proposed. Future research, particularly in large-scale studies, is needed to determine the efficiency of these aging measures and anti-aging interventions before considering their application in clinics. This review focuses on the mechanisms of cellular senescence and accelerated aging in cancer survivors, assessment of the aging process using clinical markers and biomarkers, and the high prevalence of frailty in that population, as well as possible opportunities for anti-aging interventions. A deeper understanding of aging measures and anti-aging interventions in cancer survivors will contribute to the development of effective strategies to mitigate accelerated aging in cancer survivors and improve their quality of life.
As populations worldwide show increasing levels of stress, understanding emerging links among stress, inflammation, cognition, and behavior is vital to human and planetary health. We hypothesize that inflammation is a multiscale driver connecting stressors that affect individuals to large-scale societal dysfunction and, ultimately, to planetary-scale environmental impacts. We propose a “central inflammation map” hypothesis to explain how the brain regulates inflammation and how inflammation impairs cognition, emotion, and action. According to our hypothesis, these interdependent inflammatory and neural processes, and the inter-individual transmission of environmental, infectious, and behavioral stressors—amplified via high-throughput digital global communications—can culminate in a multiscale, runaway, feed-forward process that could detrimentally affect human decision-making and behavior at scale, ultimately impairing the ability to address these same stressors. This perspective could provide non-intuitive explanations for behaviors and relationships among cells, organisms, and communities of organisms, potentially including population-level responses to stressors as diverse as global climate change, conflicts, and the COVID-19 pandemic. To illustrate our hypothesis and elucidate its mechanistic underpinnings, we present a mathematical model applicable to the individual and societal levels to test the links among stress, inflammation, control, and healing, including the implications of transmission, intervention (e.g., via lifestyle modification or medication), and resilience. Future research is needed to validate the model’s assumptions and conclusions against empirical benchmarks and to expand the factors/variables employed. Our model illustrates the need for multilayered, multiscale stress mitigation interventions, including lifestyle measures, precision therapeutics, and human ecosystem design. Our analysis shows the need for a coordinated, interdisciplinary, international research effort to understand the multiscale nature of stress. Doing so would inform the creation of interventions that improve individuals’ lives; enhance communities’ resilience to stress; and mitigate the adverse effects of stress on the world.
Purpose
This study’s primary aim was to investigate whether including a mental health component to healthy lifestyle interventions are associated with greater effects on quality of life (QoL) for post-treatment cancer survivors than addressing physical activity and/or nutrition alone.
Methods
PsycINFO, Scopus, Medline, CINAHL, and Google Scholar were searched to identify randomised control trials of healthy lifestyle interventions for post-treatment cancer survivors, with a usual care or waitlist control, and measured QoL. Meta-analyses quantified the effects of interventions vs controls at post-treatment on total QoL, physical, emotional, and social well-being. Subgroup analyses compared interventions with vs without a mental health component, modes of delivery, and duration. The quality of the included studies was assessed using the Cochrane Risk of Bias 2.
Results
Eighty-eight papers evaluating 110 interventions were included: 66 effect sizes were extracted for meta-analysis, and 22 papers were narratively synthesised. The pooled effect size demonstrated a small, significant effect of healthy lifestyle interventions in comparison to control for all QoL outcomes (total g = 0.32, p >.001; physical g = 0.19, p = 0.05; emotional g = 0.20, p >.001; social g = 0.18, p = 0.01). There was no significant difference between interventions with vs without a mental health component. Face-to-face delivered interventions were associated with greater total QoL and physical well-being compared to other modalities. Interventions delivered ≤12 weeks were associated with greater physical well-being than those delivered ≥13 weeks. Overall, studies had substantial levels of heterogeneity and 55.9% demonstrated high risk of bias.
Conclusions
Participating in a healthy lifestyle intervention following cancer treatment improves QoL. Few trials addressed mental health or evaluated online or telephone modalities; future research should develop and evaluate interventions that utilise these features.
Implications for Cancer Survivors
Brief healthy lifestyle interventions can be recommended for cancer survivors, particularly those interested in improving physical well-being.
Importance
Health care algorithms are used for diagnosis, treatment, prognosis, risk stratification, and allocation of resources. Bias in the development and use of algorithms can lead to worse outcomes for racial and ethnic minoritized groups and other historically marginalized populations such as individuals with lower income.
Objective
To provide a conceptual framework and guiding principles for mitigating and preventing bias in health care algorithms to promote health and health care equity.
Evidence Review
The Agency for Healthcare Research and Quality and the National Institute for Minority Health and Health Disparities convened a diverse panel of experts to review evidence, hear from stakeholders, and receive community feedback.
Findings
The panel developed a conceptual framework to apply guiding principles across an algorithm’s life cycle, centering health and health care equity for patients and communities as the goal, within the wider context of structural racism and discrimination. Multiple stakeholders can mitigate and prevent bias at each phase of the algorithm life cycle, including problem formulation (phase 1); data selection, assessment, and management (phase 2); algorithm development, training, and validation (phase 3); deployment and integration of algorithms in intended settings (phase 4); and algorithm monitoring, maintenance, updating, or deimplementation (phase 5). Five principles should guide these efforts: (1) promote health and health care equity during all phases of the health care algorithm life cycle; (2) ensure health care algorithms and their use are transparent and explainable; (3) authentically engage patients and communities during all phases of the health care algorithm life cycle and earn trustworthiness; (4) explicitly identify health care algorithmic fairness issues and trade-offs; and (5) establish accountability for equity and fairness in outcomes from health care algorithms.
Conclusions and Relevance
Multiple stakeholders must partner to create systems, processes, regulations, incentives, standards, and policies to mitigate and prevent algorithmic bias. Reforms should implement guiding principles that support promotion of health and health care equity in all phases of the algorithm life cycle as well as transparency and explainability, authentic community engagement and ethical partnerships, explicit identification of fairness issues and trade-offs, and accountability for equity and fairness.
Calorie restriction (CR) with adequate nutrient intake is a potential geroprotective intervention. To advance this concept in humans, we tested the hypothesis that moderate CR in healthy young‐to‐middle‐aged individuals would reduce circulating biomarkers of cellular senescence, a fundamental mechanism of aging and aging‐related conditions. Using plasma specimens from the Comprehensive Assessment of Long‐term Effects of Reducing Intake of Energy (CALERIE™) phase 2 study, we found that CR significantly reduced the concentrations of several senescence biomarkers at 12 and 24 months compared to an ad libitum diet. Using machine learning, changes in biomarker concentrations emerged as important predictors of the change in HOMA‐IR and insulin sensitivity index at 12 and 24 months, and the change in resting metabolic rate residual at 12 months. Finally, using adipose tissue RNA‐sequencing data from a subset of participants, we observed a significant reduction in a senescence‐focused gene set in response to CR at both 12 and 24 months compared to baseline. Our results advance the understanding of the effects of CR in humans and further support a link between cellular senescence and metabolic health.
Purpose
Shorter breast cancer (BC) survival outcomes persist by neighborhood disadvantage independent of patient, tumor, and treatment characteristics. This suggests unaccounted mechanisms by which neighborhood disadvantage “gets under the skin” to impact BC survival outcomes. Here, we evaluate the relationship between neighborhood disadvantage and clinical and neuroendocrine markers of stress in BC patients.
Methods
Women with stage 0–III BC were enrolled 2–10 weeks post-surgery and before initiating adjuvant treatment in a study examining stress and stress management processes. Women provided an afternoon-evening (PM) serum cortisol sample and were administered the Hamilton Anxiety Rating Scale (HAM-A). Home addresses were used to determine the Area Deprivation Index (ADI), a validated measure of neighborhood disadvantage. Multiple regression assessed the relationship between ADI and PM serum cortisol and the presence of elevated HAM-A symptoms.
Results
Our sample (n = 225) was predominately middle-aged (M = 50.4 years; range 23–70 years), non-Hispanic White (64.3%), with stage I (38.1%), or II (38.6%) disease. The majority (n = 175) lived in advantaged neighborhoods (ADI 1–3). After controlling for age, stage, and surgery type, women from high ADI (4–10) (vs low ADI) neighborhoods had higher PM cortisol levels (β = 0.19, 95% CI [0.24, 5.00], p = 0.031) and were nearly two times as likely to report the presence of elevated anxiety symptoms (OR = 1.96, 95% CI [1.00, 3.86], p = 0.050).
Conclusion
Neighborhood disadvantage is significantly associated with higher levels of PM cortisol and elevated anxiety symptoms suggesting stress pathways could potentially contribute to relationships between neighborhood disadvantage and BC survival.
Little is known regarding associations between inflammatory biomarkers and objectively measured physical activity and sleep during and after chemotherapy for gynecologic cancer; thus, we conducted a longitudinal study to address this gap. Women with gynecologic cancer (patients) and non-cancer controls (controls) completed assessments before chemotherapy cycles 1, 3, and 6 (controls assessed contemporaneously), as well as at 6- and 12-month follow-ups. Physical activity and sleep were measured using wrist-worn actigraphs and sleep diaries, and blood was drawn to quantify circulating levels of inflammatory markers. Linear and quadratic random-effects mixed models and random-effects fluctuation mixed models were used to examine physical activity and sleep over time, as well as the associations with inflammatory biomarkers. On average, patients (n = 97) and controls (n = 104) were 62 and 58 years old, respectively. Compared to controls, patients were less active, more sedentary, had more time awake after sleep onset, and had lower sleep efficiency (p-values < 0.05). Across groups, higher levels of TNF-α were associated with more sedentary time and less efficient sleep (p-values ≤ 0.05). Higher levels of IL-1β, TNF-α, and IL-6 were associated with lower levels of light physical activity (p-values < 0.05). Associations between inflammatory biomarkers, physical activity, and sleep did not differ between patients and controls. Given these results, we speculate that inflammation may contribute to less physical activity and more sleep problems that persist even 12 months after completing chemotherapy.
Epigenetic clocks are increasingly being used as a tool to assess the impact of a wide variety of phenotypes and exposures on healthy ageing, with a recent focus on social determinants of health. However, little attention has been paid to the sociodemographic characteristics of participants on whom these clocks have been based. Participant characteristics are important because sociodemographic and socioeconomic factors are known to be associated with both DNA methylation variation and healthy ageing. It is also well known that machine learning algorithms have the potential to exacerbate health inequities through the use of unrepresentative samples - prediction models may underperform in social groups that were poorly represented in the training data used to construct the model. To address this gap in the literature, we conducted a review of the sociodemographic characteristics of the participants whose data was used to construct 13 commonly used epigenetic clocks. We found that although some of the epigenetic clocks were created utilising data provided by individuals from different ages, sexes/genders, and racialized groups, sociodemographic characteristics are generally poorly reported. Reported information is limited by inadequate conceptualization of the social dimensions and exposure implications of gender and racialized inequality, and socioeconomic data is infrequently reported. It is important for future work to ensure clear reporting of tangible data on the sociodemographic and socioeconomic characteristics of all the participants in the study, to ensure other researchers can make informed judgements about the appropriateness of the model for their study population.
Purpose: Disparities in cognitive function among racial and ethnic groups have been reported in non-cancer conditions, but cancer-related cognitive impairment (CRCI) in racial and ethnic minority groups is poorly understood. We aimed to synthesize and characterize the available literature about CRCI in racial and ethnic minority populations.
Methods: We conducted a scoping review in the PubMed, PsycInfo, and Cumulative Index to Nursing and Allied Health Literature databases. Articles were included if they were published in English or Spanish, reported cognitive functioning in adults diagnosed with cancer, and characterized the race or ethnicity of the participants. Literature reviews, commentaries, letters to the editor, and gray literature were excluded.
Results: Seventy-four articles met the inclusion criteria, but only 33.8% differentiated the CRCI findings by racial or ethnic subgroups. There were associations between cognitive outcomes and the participants' race or ethnicity. Additionally, some studies found that Black and non-white individuals with cancer were more likely to experience CRCI than their white counterparts. Biological, sociocultural, and instrumentation factors were associated with CRCI differences between racial and ethnic groups. Conclusions: Our findings indicate that racial and ethnic minoritized individuals may be disparately affected by CRCI. Future research should use standardized guidelines for measuring and reporting the self-identified racial and ethnic composition of the sample; differentiate CRCI findings by racial and ethnic subgroups; consider the influence of structural racism in health outcomes; and develop strategies to promote the participation of members of racial and ethnic minority groups.
Racial and ethnic disparities in pain management pose significant challenges to equitable cancer care delivery. These disparities are driven by complex interactions between patient-, provider-, and system-related factors that resist reductionistic solutions and require innovative, holistic approaches. On September 19, 2022, the Society for Integrative Oncology (SIO) and the American Society of Clinical Oncology (ASCO) published a joint guideline to provide evidence-based recommendations on integrative medicine for cancer pain management. Integrative medicine, which combines conventional treatments with complementary modalities from cultures and traditions around the world, are uniquely equipped to resonate with diverse cancer populations and fill existing gaps in pain management. While some complementary modalities, such as music therapy and yoga, lack sufficient evidence to make a specific recommendation, other modalities, such as acupuncture, massage, and hypnosis, demonstrated an intermediate level of evidence, resulting in moderate strength recommendations for their use in cancer pain management. However, several factors may hinder real-world implementation of the SIO-ASCO guideline and must be addressed to ensure equitable pain management for all communities. These barriers include, but are not limited to, the lack of insurance coverage for many complementary therapies, the limited diversity and availability of complementary therapy providers, the negative social norms surrounding complementary therapies, the under-representation of racial and ethnic subgroups in the clinical research of complementary therapies, and the paucity of culturally attuned interventions tailored to diverse individuals. This commentary examines both the challenges and the opportunities for addressing racial and ethnic disparities in cancer pain management through integrative medicine.
Background
Cancer and its treatments may accelerate aging in survivors; however, research has not examined epigenetic markers of aging in longer term breast cancer survivors. This study examined whether older breast cancer survivors showed greater epigenetic aging than noncancer controls and whether epigenetic aging related to functional outcomes.
Methods
Nonmetastatic breast cancer survivors (n = 89) enrolled prior to systemic therapy and frequency‐matched controls (n = 101) ages 62 to 84 years provided two blood samples to derive epigenetic aging measures (Horvath, Extrinsic Epigenetic Age [EEA], PhenoAge, GrimAge, Dunedin Pace of Aging) and completed cognitive (Functional Assessment of Cancer Therapy‐Cognitive Function) and physical (Medical Outcomes Study Short Form‐12) function assessments at approximately 24 to 36 and 60 months after enrollment. Mixed‐effects models tested survivor‐control differences in epigenetic aging, adjusting for age and comorbidities; models for functional outcomes also adjusted for racial group, site, and cognitive reserve.
Results
Survivors were 1.04 to 2.22 years biologically older than controls on Horvath, EEA, GrimAge, and DunedinPACE measures (p = .001–.04) at approximately 24 to 36 months after enrollment. Survivors exposed to chemotherapy were 1.97 to 2.71 years older (p = .001–.04), and among this group, an older EEA related to worse self‐reported cognition (p = .047) relative to controls. An older epigenetic age related to worse physical function in all women (p < .001–.01). Survivors and controls showed similar epigenetic aging over time, but Black survivors showed accelerated aging over time relative to non‐Hispanic White survivors.
Conclusion
Older breast cancer survivors, particularly those exposed to chemotherapy, showed greater epigenetic aging than controls that may relate to worse outcomes. If replicated, measurement of biological aging could complement geriatric assessments to guide cancer care for older women.
Chemotherapy-induced cognitive impairment ("chemobrain") is a frequent side-effect in cancer survivors treated with paclitaxel (PTX). The mechanisms responsible for PTX-induced cognitive impairment remain obscure, and there are no effective treatments or prevention strategies. Here, we test the hypothesis that PTX induces endothelial senescence, which impairs microvascular function and contributes to the genesis of cognitive decline. We treated transgenic p16-3MR mice, which allows the detection and selective elimination of senescent cells, with PTX (5 mg/kg/day, 2 cycles; 5 days/cycle). PTX-treated and control mice were tested for spatial memory performance, neurovascular coupling (NVC) responses (whisker-stimulation-induced increases in cerebral blood flow), microvascular density, blood-brain barrier (BBB) permeability and the presence of senescent endothelial cells (by flow cytometry and single-cell transcriptomics) at 6 months post-treatment. PTX induced senescence in endothelial cells, which associated with microvascular rarefaction, NVC dysfunction, BBB disruption, neuroinflammation, and impaired performance on cognitive tasks. To establish a causal relationship between PTX-induced senescence and impaired microvascular functions, senescent cells were depleted from PTX-treated animals (at 3 months post-treatment) by genetic (ganciclovir) or pharmacological (treatment with the senolytic drug ABT263/Navitoclax) means. In PTX treated mice, both treatments effectively eliminated senescent endothelial cells, rescued endothelium-mediated NVC responses and BBB integrity, increased capillarization and improved cognitive performance. Our findings suggest that senolytic treatments can be a promising strategy for preventing chemotherapy-induced cognitive impairment.
Background
Allostatic load (AL) has been linked to an increased risk of death in various populations. However, to date, there is no research specifically investigating the effect of AL on mortality in older cancer survivors.
Aims
To investigate the association between AL and mortality in older cancer survivors.
Method
A total of 1291 adults aged 60 years or older who survived for ≥1 year since cancer diagnoses were identified from the 1999 to 2010 National Health and Nutrition Examination Survey. AL was the exposure of interest incorporating nine clinical measures/biomarkers; one point was added to AL if any of the measures/biomarkers exceeded the normal level. The sum of points was categorized as an ordinal variable to reflect low, moderate, and high ALs. Our outcomes of interest were all‐cause, cancer‐specific, and cardiovascular disease–specific mortality. Death was identified by linkage to the National Death Index. Multivariable Cox proportional hazards models were used to estimate adjusted hazard ratio (aHR) and 95% confidence intervals (CI) of mortality by AL category.
Results
Overall, 53.6% of participants were male and 78.4% were white. The mean age of study participants at interview was 72.8 years (standard deviation = 7.1). A total of 546 participants died during the follow‐up (median follow‐up time: 8.0 years). Among them, 158 died of cancer, and 106 died of cardiovascular events. Results from multivariable Cox proportional hazards models showed that higher ALS was positively associated with higher all‐cause mortality (ALS = 4–9 vs. ALS = 0–1: aHR = 1.52, 95% CI = 1.17–1.98, p‐trend < 0.01) and higher cancer‐specific mortality (ALS = 4–9 vs. ALS = 0–1: aHR = 1.80, 95% CI = 1.12–2.90, p‐trend = 0.01). The association between ALS and cardiovascular mortality was positive but nonsignificant (ALS = 4–9 vs. ALS = 0–1: aHR = 1.59, 95% CI = 0.86–2.94, p‐trend = 0.11).
Conclusions
Our study suggests that older cancer survivors can have a higher risk of death if they have a high burden of AL.
Objective: Racial and ethnic disparities in smoking cessation persist. This randomized controlled trial compared the efficacy of group cognitive behavioral therapy (CBT) for cessation among African American/Black, Latino/Hispanic, and White adults. Method: African American/Black (39%), Latino/Hispanic (29%), and White (32%) adults (N = 347) were randomly assigned to eight group sessions of CBT or general health education (GHE), both including nicotine patch therapy. Biochemically confirmed 7-day point prevalence abstinence (7-day ppa) was measured at the end-of-therapy, and at 3-, 6-, and 12-month follow-ups. Generalized linear mixed models and logistic regressions tested abstinence rates by condition, stratified by race and ethnicity, and interaction effects. Results: CBT led to greater abstinence than GHE across 12-months of follow-up (AOR = 1.84, 95% CI [1.59, 2.13]) overall [12-month follow-up: CBT = 54% vs. GHE = 38%] and within racial and ethnic groups [12-months: African American/Black (CBT = 52%, GHE = 29%), Latino/Hispanic (CBT = 57%, GHE = 47%), and White (CBT = 54%, GHE = 41%)]. African American participants were less likely than White participants to quit irrespective of condition, as were persons with lower education and income. Socioeconomic status indicators positively predicted abstinence among racial and ethnic minority participants, but not White participants. Conclusions: Group CBT was efficacious compared with GHE. However, cessation patterns suggested that intensive group interventions were less beneficial over the longer term among lower socioeconomic African American and Latino individuals, compared with White participants. Tobacco interventions should target racial and ethnic and socioeconomic differences, via culturally specific approaches and other means.
Background
Immune activation/inflammation markers (immune markers) were tested to explain differences in neurocognition among older breast cancer survivors versus noncancer controls.
Methods
Women >60 years old with primary breast cancer (stages 0–III) (n = 400) were assessed before systemic therapy with frequency‐matched controls (n = 329) and followed annually to 60 months; blood was collected during annual assessments from 2016 to 2020. Neurocognition was measured by tests of attention, processing speed, and executive function (APE). Plasma levels of interleukin‐6 (IL‐6), IL‐8, IL‐10, tumor necrosis factor α (TNF‐α), and interferon γ were determined using multiplex testing. Mixed linear models were used to compare results of immune marker levels by survivor/control group by time and by controlling for age, racial/ethnic group, cognitive reserve, and study site. Covariate‐adjusted multilevel mediation analyses tested whether survivor/control group effects on cognition were explained by immune markers; secondary analyses examined the impact of additional covariates (e.g., comorbidity and obesity) on mediation effects.
Results
Participants were aged 60–90 years (mean, 67.7 years). Most survivors had stage I (60.9%) estrogen receptor–positive tumors (87.6%). Survivors had significantly higher IL‐6 levels than controls before systemic therapy and at 12, 24, and 60 months (p ≤ .001–.014) but there were no differences for other markers. Survivors had lower adjusted APE scores than controls (p < .05). Levels of IL‐6, IL‐10, and TNF‐α were related to APE, with IL‐6 explaining part of the relationship between survivor/control group and APE (p = .01). The magnitude of this mediation effect decreased but remained significant (p = .047) after the consideration of additional covariates.
Conclusions
Older breast cancer survivors had worse long‐term neurocognitive performance than controls, and this relationship was explained in part by elevated IL‐6.
Purpose
To evaluate the association of subjective social status (SSS) with metabolic syndrome (MetS) severity and its potential contribution to racial health disparities in women with breast cancer.
Methods
Multicenter cross-sectional study (10 US hospitals) in women (n = 1206) with primary diagnosis of invasive breast cancer received during Mar/2013–Feb/2020. Participants, self-identified as non-Hispanic White or Black, underwent physical and laboratory examinations and survey questions assessing socioeconomic parameters, medical history, and behavioral risks. SSS was measured with the 10-rung MacArthur scale. MetS severity was measured with a validated Z-Score. Generalized linear mixed modeling was used to analyze the associations. Missing data were handled using multiple imputation.
Results
Average age was 58 years. On average, the SSS of Black women, given equivalent level of income and education, was lower than the SSS of White women: 6.6 (6.1–7.0) vs 7.7 (7.54–7.79) among college graduates and 6.8 (6.4–7.2) vs 7.6 (7.5–7.8) among women in the high-income category (> $75,000). In multivariable analysis, after controlling for age, income, education, diet, and physical activity, increasing SSS was associated with a decrease in MetS-Z score, − 0.10 (− 0.16 to − 0.04) per every 2 rung increase in the MacArthur scale.
Conclusion
Black women with breast cancer rank their SSS lower than White women with breast cancer do at each level of income and education. As SSS is strongly associated with MetS severity these results identify potentially modifiable factors that contribute to racial disparities.
Importance:
Neighborhood-level disadvantage is an important factor in the creation and persistence of underresourced neighborhoods with an undue burden of disparate breast cancer-specific survival outcomes. Although studies have evaluated neighborhood-level disadvantage and breast cancer-specific survival after accounting for individual-level socioeconomic status (SES) in large national cancer databases, these studies are limited by age, socioeconomic, and racial and ethnic diversity.
Objective:
To investigate neighborhood SES (using a validated comprehensive composite measure) and breast cancer-specific survival in a majority-minority population.
Design, setting, and participants:
This retrospective multi-institutional cohort study included patients with stage I to IV breast cancer treated at a National Cancer Institute-designated cancer center and sister safety-net hospital from January 10, 2007, to September 9, 2016. Mean (SD) follow-up time was 60.3 (41.4) months. Data analysis was performed from March 2022 to March 2023.
Exposures:
Neighborhood SES was measured using the Area Deprivation Index (tertiles), a validated comprehensive composite measure of neighborhood SES.
Main outcomes and measures:
The primary outcome was breast cancer-specific survival. Random effects frailty models for breast cancer-specific survival were performed controlling for individual-level sociodemographic, comorbidity, breast cancer risk factor, access to care, tumor, and National Comprehensive Cancer Network guideline-concordant treatment characteristics. The Area Deprivation Index was calculated for each patient at the census block group level and categorized into tertiles (T1-T3).
Results:
A total of 5027 women with breast cancer were included: 55.8% were Hispanic, 17.5% were non-Hispanic Black, and 27.0% were non-Hispanic White. Mean (SD) age was 55.5 (11.7) years. Women living in the most disadvantaged neighborhoods (T3) had shorter breast cancer-specific survival compared with those living in the most advantaged neighborhoods (T1) after controlling for individual-level sociodemographic, comorbidity, breast cancer risk factor, access to care, tumor, and National Comprehensive Cancer Network guideline-concordant treatment characteristics (T3 vs T1: hazard ratio, 1.29; 95% CI, 1.01-1.65; P < .04).
Conclusions and relevance:
In this cohort study, a shorter breast cancer-specific survival in women from disadvantaged neighborhoods compared with advantaged neighborhoods was identified, even after controlling for individual-level sociodemographic, comorbidity, breast cancer risk factor, access to care, tumor, and National Comprehensive Cancer Network guideline-concordant treatment characteristics. The findings suggest potential unaccounted mechanisms, including unmeasured social determinants of health and access to care measures. This study also lays the foundation for future research to evaluate whether social adversity from living in a disadvantaged neighborhood is associated with more aggressive tumor biologic factors, and ultimately shorter breast cancer-specific survival, through social genomic and/or epigenomic alterations.
Background
Breast (BCa) and prostate (PCa) cancer are two of the most common but survivable cancers. One important component of survivorship that is impacted by treatment long term is diminished quality of life (QoL). Supervised exercise improves QoL and subsequent outcomes but is not accessible for all survivors. Additionally, many factors influence QoL including physical activity (PA), cardiorespiratory fitness (CRF), physical function, and fatigue. However, the COVID-19 pandemic has highlighted the need to increase access to exercise beyond supervised exercise facilities. Home-based exercise may provide a feasible alternative for cancer survivors especially for those living in rural communities.
Objectives
The primary aim is to investigate the effects of home-based exercise training (Pre-training vs. Post-training) on QoL in BCa/PCa. A secondary aim is to investigate PA, CRF, physical function, and fatigue and potential moderators (age, cancer-type, intervention duration and type). Home-based exercise trials (randomized crossover or quasi-experimental design) with adults (aged 18 years and over) breast or prostate cancer survivors (not currently undergoing chemotherapy or radiation treatment) were eligible for inclusion.
Data sources
Electronic databases were searched (inception-December 2022) for studies which included adult BCa or PCa survivors (not currently on chemotherapy/radiation), at least measured QoL, and undergoing unsupervised, home-based exercise training.
Appraisal and synthesis methods
Initially, 819 studies were identified, from which 17 studies (20 effects) involving 692 participants were extracted. Effect sizes were calculated as standardized mean differences (SMD). Data were pooled using a 3-level model with restricted maximum likelihood estimation. Pooled SMD was used to assess the magnitude of effect, where <0.2, 0.2, 0.5, and 0.8 was defined as trivial, small, moderate, and large respectively.
Results
Home-based exercise resulted in small improvements in QoL (SMD = 0.30, 95% CI 0.01, 0.60, p = 0.042), PA (SMD = 0.49, 95% CI 0.26, 0.75, p<0.001) and CRF (SMD = 0.45, 95% CI -0.01, 0.91, p = 0.056). Physical function (SMD = 0.00, 95% CI -0.21, 0.21, p = 1.000) and fatigue (SMD = -0.61, 95%CI -1.53, 0.32, p = 0.198) did not change.
Conclusions
Home-based exercise results in small improves QoL in BCa/PCa survivors, independent of cancer type, intervention duration and type, or age. Home-based exercise also improves PA and CRF enhancing survivorship. Therefore, home-based exercise is an efficacious alternative option to improve QoL for BCa and PCa survivors especially for those who live in rural communities or lack access to exercise facilities.
Background:
Starting in 2018, national death certificates included a new racial classification system that accounts for multiple-race decedents and separates Native Hawaiian and Pacific Islander (NHPI) individuals from Asian individuals. We estimated cancer death rates across updated racial/ethnic categories, sex, and age.
Methods:
Age-standardized U.S. cancer mortality rates and rate ratios from 2018-2020 among ≥20-year-olds were estimated with national death certificate data by race/ethnicity, sex, age, and cancer site.
Results:
In 2018, there were approximately 597,000 cancer deaths, 598,000 in 2019, and 601,000 in 2020. Among men, cancer death rates were highest in Black men (298.2/100,000; n = 105,632), followed by White (250.8; n = 736,319), American Indian/Alaska Native (AI/AN) (249.2; n = 3,376), NHPI (205.6; n = 1,080), Latino (177.2; n = 66,167), and Asian (147.9; n = 26,591) men. Among women, Black women had the highest cancer death rates (206.5/100,000; n = 104,437), followed by NHPI (192.1; n = 1,141), AI/AN (189.9; n = 3,239), White (183.0; n = 646,865), Latina (128.4; n = 61,579), and Asian women (111.4; n = 26,396). The highest death rates by age group occurred among NHPI individuals aged 20-49 years, and Black individuals aged 50-69 and ≥70 years. Asian individuals had the lowest cancer death rates across age groups. Compared to Asian individuals, total cancer death rates were 39% higher in NHPI men and 73% higher in NHPI women.
Conclusions:
There were striking racial/ethnic disparities in cancer death rates during 2018-2020. Separating NHPI and Asian individuals revealed large differences in cancer mortality between two groups that were previously combined in vital statistics data.
Rapamycin (sirolimus) and other rapalogs (everolimus) are anti-cancer and anti-aging drugs, which delay cancer by directly targeting pre-cancerous cells and, indirectly, by slowing down organism aging. Cancer is an age-related disease and, figuratively, by slowing down time (and aging), rapamycin may delay cancer. In several dozen murine models, rapamycin robustly and reproducibly prevents cancer. Rapamycin slows cell proliferation and tumor progression, thus delaying the onset of cancer in carcinogen-treated, genetically cancer-prone and normal mice. Data on the use of rapamycin and everolimus in organ-transplant patients are consistent with their cancer-preventive effects. Treatment with rapamycin was proposed to prevent lung cancer in smokers and former smokers. Clinical trials in high-risk populations are warranted.
Background
Discrimination can adversely affect health and accelerate aging, but little is known about these relationships in cancer survivors. This study examines associations of discrimination and aging among self‐identified African American survivors.
Methods
A population‐based sample of 2232 survivors 20–79 years old at diagnosis were enrolled within 5 years of breast (n = 787), colorectal (n = 227), lung (n = 223), or prostate (n = 995) cancer between 2017 and 2022. Surveys were completed post‐active therapy. A deficit accumulation index measured aging‐related disease and function (score range, 0–1, where <0.20 is robust, 0.20 to <0.35 is pre‐frail, and 0.35+ is frail; 0.06 is a large clinically meaningful difference). The discrimination scale assessed ever experiencing major discrimination and seven types of events (score, 0–7). Linear regression tested the association of discrimination and deficit accumulation, controlling for age, time from diagnosis, cancer type, stage and therapy, and sociodemographic variables.
Results
Survivors were an average of 62 years old (SD, 9.6), 63.2% reported ever experiencing major discrimination, with an average of 2.4 (SD, 1.7) types of discrimination events. Only 24.4% had deficit accumulation scores considered robust (mean score, 0.30 [SD, 0.13]). Among those who reported ever experiencing major discrimination, survivors with four to seven types of discrimination events (vs. 0–1) had a large, clinically meaningful increase in adjusted deficits (0.062, p < .001) and this pattern was consistent across cancer types.
Conclusion
African American cancer survivors have high deficit accumulated index scores, and experiences of major discrimination were positively associated with these deficits. Future studies are needed to understand the intersectionality between aging, discrimination, and cancer survivorship among diverse populations.
The ageing process is a systemic decline from cellular dysfunction to organ degeneration, with more predisposition to deteriorated disorders. Rejuvenation refers to giving aged cells or organisms more youthful characteristics through various techniques, such as cellular reprogramming and epigenetic regulation. The great leaps in cellular rejuvenation prove that ageing is not a one-way street, and many rejuvenative interventions have emerged to delay and even reverse the ageing process. Defining the mechanism by which roadblocks and signaling inputs influence complex ageing programs is essential for understanding and developing rejuvenative strategies. Here, we discuss the intrinsic and extrinsic factors that counteract cell rejuvenation, and the targeted cells and core mechanisms involved in this process. Then, we critically summarize the latest advances in state-of-art strategies of cellular rejuvenation. Various rejuvenation methods also provide insights for treating specific ageing-related diseases, including cellular reprogramming, the removal of senescence cells (SCs) and suppression of senescence-associated secretory phenotype (SASP), metabolic manipulation, stem cells-associated therapy, dietary restriction, immune rejuvenation and heterochronic transplantation, etc. The potential applications of rejuvenation therapy also extend to cancer treatment. Finally, we analyze in detail the therapeutic opportunities and challenges of rejuvenation technology. Deciphering rejuvenation interventions will provide further insights into anti-ageing and ageing-related disease treatment in clinical settings.
Geroscience posits that molecular drivers underlie the aging process. Gerotherapeutics entail strategies to counter molecular drivers of aging to reduce the chronic diseases and geriatric syndromes they trigger. Although the concept of gerotherapeutics for prevention has generated much excitement, the implications of prescribing potentially harmful medications to older adults who are “healthy” have been associated with many delays. Concerns regarding safety and valid endpoints have contributed to holdups. In contrast, it has been relatively easier to implement trials of medications with gerotherapeutic properties as novel approaches to remedy disease. In these applications, the risks of the medications are easier to justify when therapeutic benefits are perceived as outweighing the harms of the disease. Likewise, metrics of effective disease treatments are often seen as more reliable and quantifiable than metrics of health prolongation. Overall, clarifying geroscience mechanisms in disease therapeutic applications provides key opportunities to advance translational geroscience, especially as preventive geroscience trials are often encumbered. In this review, gerotherapeutic benefits of canakinumab, cholchicine, and zoledronic acid as parts of disease management are considered. Longevity Clinics and other opportunities to advance translational geroscience as parts of contemporary care are also discussed.
PURPOSE
It is unknown whether Medicaid expansion under the Affordable Care Act (ACA) or state-level policies mandating Medicaid coverage of the routine costs of clinical trial participation have ameliorated longstanding racial and ethnic disparities in cancer clinical trial enrollment.
METHODS
We conducted a retrospective, cross-sectional difference-in-differences analysis examining the effect of Medicaid expansion on rates of enrollment for Black or Hispanic nonelderly adults in nonobservational, US cancer clinical trials using data from Medidata's Rave platform for 2012-2019. We examined heterogeneity in this effect on the basis of whether states had pre-existing mandates requiring Medicaid coverage of the routine costs of clinical trial participation.
RESULTS
The study included 47,870 participants across 1,353 clinical trials and 344 clinical trial sites. In expansion states, the proportion of participants who were Black or Hispanic increased from 16.7% before expansion to 17.2% after Medicaid expansion (0.5 percentage point [PP] change [95% CI, –1.1 to 2.0]). In nonexpansion states, this proportion increased from 19.8% before 2014 (when the first states expanded eligibility under the ACA) to 20.4% after 2014 (0.6 PP change [95% CI, –2.3 to 3.5]). These trends yielded a nonsignificant difference-in-differences estimate of 0.9 PP (95% CI, –2.6 to 4.4). Medicaid expansion was associated with a 5.3 PP (95% CI, 1.9 to 8.7) increase in the enrollment of Black or Hispanic participants in states with mandates requiring Medicaid coverage of the routine costs of trial participation, but not in states without mandates (–0.3 PP [95% CI, –4.5 to 3.9]).
CONCLUSION
Medicaid expansion was not associated with a significant increase in the proportion of Black or Hispanic oncology trial participants overall, but was associated with an increase specifically in states that mandated Medicaid coverage of the routine costs of trial participation.
Importance
African American men experience greater prostate cancer incidence and mortality than White men. Growing literature supports associations of neighborhood disadvantage, which disproportionately affects African American men, with aggressive prostate cancer; chronic stress and downstream biological impacts (eg, increased inflammation) may contribute to these associations.
Objective
To examine whether several neighborhood disadvantage metrics are associated with prostate tumor RNA expression of stress-related genes.
Design, Setting, and Participants
This cross-sectional study leveraged prostate tumor transcriptomic data for African American and White men with prostate cancer who received radical prostatectomy at the University of Maryland Medical Center between August 1992 and January 2021. Data were analyzed from May 2023 to April 2024.
Exposures
Using addresses at diagnosis, 2 neighborhood deprivation metrics (Area Deprivation Index [ADI] and validated bayesian Neighborhood Deprivation Index) as well as the Racial Isolation Index (RI) and historical redlining were applied to participants’ addresses. Self-reported race was determined using electronic medical records.
Main Outcomes and Measures
A total of 105 stress-related genes were evaluated with each neighborhood metric using linear regression, adjusting for race, age, and year of surgery. Genes in the Conserved Transcriptional Response to Adversity (CTRA) and stress-related signaling genes were included.
Results
A total of 218 men (168 [77%] African American, 50 [23%] White) with a median (IQR) age of 58 (53-63) years were included. African American participants experienced greater neighborhood disadvantage than White participants (median [IQR] ADI, 115 [100-130] vs 92 [83-104]; median [IQR] RI, 0.68 [0.34-0.87] vs 0.11 [0.06-0.14]). ADI was positively associated with expression for 11 genes; HTR6 (serotonin pathway) remained significant after multiple-comparison adjustment (β = 0.003; SE, 0.001; P < .001; Benjamini-Hochberg q value = .01). Several genes, including HTR6 , were associated with multiple metrics. We observed higher expression of 5 proinflammatory genes in the CTRA with greater neighborhood disadvantage (eg, CXCL8 and ADI, β = 0.008; SE, 0.003; P = .01; q value = .21).
Conclusions and Relevance
In this cross-sectional study, the expression of several stress-related genes in prostate tumors was higher among men residing in disadvantaged neighborhoods. This study is one of the first to suggest associations of neighborhood disadvantage with prostate tumor RNA expression. Additional research is needed in larger studies to replicate findings and further investigate interrelationships of neighborhood factors, tumor biology, and aggressive prostate cancer to inform interventions to reduce disparities.
Advances in cancer prevention, early detection and treatments have led to unprecedented progress against cancer. However, these advances have not benefited everyone equally. Because of a long history of structural inequities and systemic injustices in the United States, many segments of the US population continue to shoulder a disproportionate burden of cancer. The American Association for Cancer Research (AACR) Cancer Disparities Progress Report 2024 (CancerDisparitiesProgressReport.org) outlines the recent progress against cancer disparities, the ongoing challenges faced by medically underserved populations, and emphasizes the vital need for further advances in cancer research and patient care to benefit all populations.
Introduction
Cancer health disparities are widespread. Nevertheless, the disparities in outcomes among diverse survivors of cancer ages 65 years and older (“older”) have not been systematically evaluated.
Methods
We conducted a scoping review of original research articles published between January 2016 and September 2023 and indexed in Medline (Ovid), Embase, Scopus, and CINAHL databases. We included studies evaluating racial, ethnic, socioeconomic disadvantaged, geographic, sexual and gender, and/or persons with disabilities disparities in treatment, survivorship, and mortality among older survivors of cancer. We excluded studies with no a priori aims related to a health disparity, review articles, conference proceedings, meeting abstracts, studies with unclear methodologies, and articles in which the disparity group was examined only as an analytic covariate. Two reviewers independently extracted data following the Preferred Reporting Items for Systematic Reviews and Meta‐Analysis reporting guidelines.
Results
After searching and removing duplicates, 2573 unique citations remained and after screening 59 articles met the inclusion criteria. Many investigated more than one health disparity, and most focused on racial and ethnic ( n = 44) or socioeconomic ( n = 25) disparities; only 10 studies described geographic disparities, and none evaluated disparities in persons with disabilities or due to sexual and gender identity. Research investigating disparities in outcomes among diverse older survivors of cancer is increasing gradually—68% of eligible articles were published between 2020 and 2023. Most studies focused on the treatment phase of care ( n = 28) and mortality ( n = 26), with 16 examined disparities in survivorship, symptoms, or quality of life. Most research was descriptive and lacked analyses of potential underlying mechanisms contributing to the reported disparities.
Conclusion
Little research has evaluated the effect of strategies to reduce health disparities among older patients with cancer. This lack of evidence perpetuates cancer inequities and leaves the cancer care system ill equipped to address the unique needs of the rapidly growing and increasingly diverse older adult cancer population.
Objective
To determine the association between objective (geospatial) and subjective (perceived) measures of neighborhood disadvantage (ND) and aggressive breast cancer (BCa) tumor biology, defined using validated social adversity-associated transcription factor (TF) activity and clinical outcomes.
Summary Background Data
ND is associated with shorter BCa recurrence-free survival (RFS), independent of individual, tumor, and treatment characteristics, suggesting potential unaccounted biological mechanisms by which ND influences RFS.
Methods
We quantified TF-binding motif prevalence within promoters of differentially expressed genes for 147 tissue samples prospectively collected on protocol. Covariate-adjusted multivariable regression analyzed objective and subjective ND scores with 5 validated TFs of social adversity and aggressive biology—pro-inflammatory activity (NF-kB, AP-1), sympathetic nervous system (SNS) activity (CREB), and protective cellular responses (IRF, STAT). To clinically validate these TFs as prognostic biomarkers of aggressive biology, logistic regression and multivariable Cox proportional-hazards models analyzed their association with Oncotype DX scores and RFS, respectively.
Results
Increasing objective ND was associated with aggressive tumor biology (up-regulated NF-kB, AP-1, down-regulated IRF, STAT) and SNS activation (up-regulated CREB). Increasing subjective ND (e.g., threat to safety), was associated with up-regulated NF-kB and CREB and down-regulated IRF. These TF patterns were associated with high-risk Oncotype DX scores and shorter RFS.
Conclusions
In the largest human social genomics study, objective and subjective ND were significantly associated with TFs of aggressive biology and SNS activation. These TFs also correlated with worse clinical outcomes, implicating SNS activation as one potential mechanism behind ND survival disparities. These findings remain to be validated in a national cohort.
The proportion of older adults in the U.S. is growing, and the older adult population is also becoming increasingly diverse. However, there are limited data on the aging process and older adults in underserved populations. Equitable participation in research studies on aging, the research workforce, and the healthcare workforce is critical to improve health outcomes for the entire U.S. population. Health disparities frameworks offer researchers and healthcare professionals the tools to develop and evaluate aging research that addresses all levels of analysis and domains of influence. Although there have been efforts to diversify the healthcare and research workforce, significant disparities in representation remain. In this perspective, we discuss existing aging health disparities, health disparities frameworks to use as tools to better conduct aging research, methods to enhance the proportion of underrepresented populations in aging research, and the current gaps in as well as efforts to enhance the diversity of the healthcare and research workforces.
The search for biomarkers that quantify biological aging (particularly 'omic'-based biomarkers) has intensified in recent years. Such biomarkers could predict aging-related outcomes and could serve as surrogate endpoints for the evaluation of interventions promoting healthy aging and longevity. However, no consensus exists on how biomarkers of aging should be validated before their translation to the clinic. Here, we review current efforts to evaluate the predictive validity of omic biomarkers of aging in population studies, discuss challenges in comparability and generalizability and provide recommendations to facilitate future validation of biomarkers of aging. Finally, we discuss how systematic validation can accelerate clinical translation of biomarkers of aging and their use in gerotherapeutic clinical trials.
Over the past 2 decades, population simulation modeling has evolved as an effective public health tool for surveillance of cancer trends and estimation of the impact of screening and treatment strategies on incidence and mortality, including documentation of persistent cancer inequities. The goal of this research was to provide a framework to support the next generation of cancer population simulation models to identify leverage points in the cancer control continuum to accelerate achievement of equity in cancer care for minoritized populations. In our framework, systemic racism is conceptualized as the root cause of inequity and an upstream influence acting on subsequent downstream events, which ultimately exert physiological effects on cancer incidence and mortality and competing comorbidities. To date, most simulation models investigating racial inequity have used individual-level race variables. Individual-level race is a proxy for exposure to systemic racism, not a biological construct. However, single-level race variables are suboptimal proxies for the multilevel systems, policies, and practices that perpetuate inequity. We recommend that future models designed to capture relationships between systemic racism and cancer outcomes replace or extend single-level race variables with multilevel measures that capture structural, interpersonal, and internalized racism. Models should investigate actionable levers, such as changes in health care, education, and economic structures and policies to increase equity and reductions in health-care–based interpersonal racism. This integrated approach could support novel research approaches, make explicit the effects of different structures and policies, highlight data gaps in interactions between model components mirroring how factors act in the real world, inform how we collect data to model cancer equity, and generate results that could inform policy.
Purpose
Structural racism could contribute to racial and ethnic disparities in cancer mortality via its broad effects on housing, economic opportunities, and health care. However, there has been limited focus on incorporating structural racism into simulation models designed to identify practice and policy strategies to support health equity. We reviewed studies evaluating structural racism and cancer mortality disparities to highlight opportunities, challenges, and future directions to capture this broad concept in simulation modeling research.
Methods
We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Scoping Review Extension guidelines. Articles published between 2018 and 2023 were searched including terms related to race, ethnicity, cancer-specific and all-cause mortality, and structural racism. We included studies evaluating the effects of structural racism on racial and ethnic disparities in cancer mortality in the United States.
Results
A total of 8345 articles were identified, and 183 articles were included. Studies used different measures, data sources, and methods. For example, in 20 studies, racial residential segregation, one component of structural racism, was measured by indices of dissimilarity, concentration at the extremes, redlining, or isolation. Data sources included cancer registries, claims, or institutional data linked to area-level metrics from the US census or historical mortgage data. Segregation was associated with worse survival. Nine studies were location specific, and the segregation measures were developed for Black, Hispanic, and White residents.
Conclusions
A range of measures and data sources are available to capture the effects of structural racism. We provide a set of recommendations for best practices for modelers to consider when incorporating the effects of structural racism into simulation models.
Despite significant progress in cancer research and treatment, a persistent knowledge gap exists in understanding and addressing cancer care disparities, particularly among populations that are marginalized. This knowledge deficit has led to a “data divide,” where certain groups lack adequate representation in cancer-related data, hindering their access to personalized and data-driven cancer care. This divide disproportionately affects marginalized and minoritized communities such as the U.S. Black population. We explore the concept of “data deserts,” wherein entire populations, often based on race, ethnicity, gender, disability, or geography, lack comprehensive and high-quality health data. Several factors contribute to data deserts, including underrepresentation in clinical trials, poor data quality, and limited access to digital technologies, particularly in rural and lower-socioeconomic communities.The consequences of data divides and data deserts are far-reaching, impeding equitable access to precision medicine and perpetuating health disparities. To bridge this divide, we highlight the role of the Cancer Intervention and Surveillance Modeling Network (CISNET), which employs population simulation modeling to quantify cancer care disparities, particularly among the U.S. Black population. We emphasize the importance of collecting quality data from various sources to improve model accuracy. CISNET's collaborative approach, utilizing multiple independent models, offers consistent results and identifies gaps in knowledge. It demonstrates the impact of systemic racism on cancer incidence and mortality, paving the way for evidence-based policies and interventions to eliminate health disparities. We suggest the potential use of voting districts/precincts as a unit of aggregation for future CISNET modeling, enabling targeted interventions and informed policy decisions.
Background
With two well‐validated aging measures capturing mortality and morbidity risk, this study examined whether and to what extent aging mediates the associations of unhealthy lifestyles with adverse health outcomes.
Methods
Data were from 405,944 adults (40–69 years) from UK Biobank (UKB) and 9972 adults (20–84 years) from the US National Health and Nutrition Examination Survey (NHANES). An unhealthy lifestyles score (range: 0–5) was constructed based on five factors (smoking, drinking, physical inactivity, unhealthy body mass index, and unhealthy diet). Two aging measures, Phenotypic Age Acceleration (PhenoAgeAccel) and Biological Age Acceleration (BioAgeAccel) were calculated using nine and seven blood biomarkers, respectively, with a higher value indicating the acceleration of aging. The outcomes included incident cardiovascular disease (CVD), incident cancer, and all‐cause mortality in UKB; CVD mortality, cancer mortality, and all‐cause mortality in NHANES. A general linear regression model, Cox proportional hazards model, and formal mediation analysis were performed.
Results
The unhealthy lifestyles score was positively associated with PhenoAgeAccel (UKB: β = 0.741; NHANES: β = 0.874, all p < 0.001). We further confirmed the respective associations of PhenoAgeAccel and unhealthy lifestyles with the outcomes in UKB and NHANES. The mediation proportion of PhenoAgeAccel in associations of unhealthy lifestyles with incident CVD, incident cancer, and all‐cause mortality were 20.0%, 17.8%, and 26.6% (all p < 0.001) in UKB, respectively. Similar results were found in NHANES. The findings were robust when using another aging measure—BioAgeAccel.
Conclusions
Accelerated aging partially mediated the associations of lifestyles with CVD, cancer, and mortality in UK and US populations. The findings reveal a novel pathway and the potential of geroprotective programs in mitigating health inequality in late life beyond lifestyle interventions.
We are facing a growing aging population, along with increasing pressure on health systems, caused by the impact of chronic co-morbidities (i.e. cancer, cardiovascular and neurodegenerative diseases) and functional disabilities as people age. Relatively simple preventive lifestyle interventions, such as dietary restriction and physical exercise, are important contributors to active and healthy aging in the general population. However, as shown in model organisms or in 'in vitro' conditions, lifestyle-independent interventions may have additional health benefits and can even be conceived as possible reversers of the aging process. Thus, pharmaceutical laboratories, research institutes, and universities are putting more and more effort into finding new molecular pathways and druggable targets to develop gerotherapeutics. One approach is to target the driving mechanisms of aging, some of which, like cellular senescence and impaired autophagy, we discussed in an update on the biology of aging at AgingFit 2023 in Lille, France. We underline the importance of carefully and extensively testing senotherapeutics, given the pleiotropism and heterogeneity of targeted senescent cells within different organs, at different time frames. Other druggable targets emerging from new putative mechanisms, like those based on transcriptome imbalance, nucleophagy, protein phosphatase depletion, glutamine metabolism, or seno-antigenicity, have been evidenced by recent preclinical studies in classical models of aging but need to be validated in humans. Finally, we highlight several approaches in the discovery of biomarkers of healthy aging, as well as for the prediction of neurodegenerative diseases and the evaluation of rejuvenation strategies.
Purpose:
To update the ASCO guideline (2018) on the practical assessment and management of age-associated vulnerabilities in older patients undergoing systemic cancer therapy.
Methods:
An Expert Panel conducted a systematic review to identify relevant randomized clinical trials (RCTs), systematic reviews, and meta-analyses from January 2016 to December 2022.
Results:
A total of 26 publications met eligibility criteria and form the evidentiary basis for the update.
Recommendations:
The Expert Panel reiterates its overarching recommendation from the prior guideline that geriatric assessment (GA), including all essential domains, should be used to identify vulnerabilities or impairments that are not routinely captured in oncology assessments for all patients over 65 years old with cancer. Based on recently published RCTs demonstrating significantly improved clinical outcomes, all older adults with cancer (65+ years old) receiving systemic therapy with GA-identified deficits should have GA-guided management (GAM) included in their care plan. GAM includes using GA findings to inform cancer treatment decision-making as well as to address impairments through appropriate interventions, counseling, and/or referrals. A GA should include high priority aging-related domains known to be associated with outcomes in older adults with cancer: physical and cognitive function, emotional health, comorbid conditions, polypharmacy, nutrition, and social support. Clinical adaptation of the GA based on patient population, resources, and time is appropriate.The Panel recommends the Practical Geriatric Assessment as one option for this purpose (https://old-prod.asco.org/sites/new-www.asco.org/files/content-files/practice-patients/documents/2023-PGA-Final.pdf; https://youtu.be/jnaQIjOz2Dw; https://youtu.be/nZXtwaGh0Z0).Additional information is available at www.asco.org/supportive-care-guidelines.
A hallmark of eukaryotic aging is a loss of epigenetic information, a process that can be reversed. We have previously shown that the ectopic induction of the Yamanaka factors OCT4, SOX2, and KLF4 (OSK) in mammals can restore youthful DNA methylation patterns, transcript profiles, and tissue function, without erasing cellular identity, a process that requires active DNA demethylation. To screen for molecules that reverse cellular aging and rejuvenate human cells without altering the genome, we developed high-throughput cell-based assays that distinguish young from old and senescent cells, including transcription-based aging clocks and a real-time nucleocytoplasmic compartmentalization (NCC) assay. We identify six chemical cocktails, which, in less than a week and without compromising cellular identity, restore a youthful genome-wide transcript profile and reverse transcriptomic age. Thus, rejuvenation by age reversal can be achieved, not only by genetic, but also chemical means.
Targeting aging is the future of twenty-first century preventative medicine. Small molecule interventions that promote healthy longevity are known, but few are well-developed and discovery of novel, robust interventions has stagnated. To accelerate longevity intervention discovery and development, high-throughput systems are needed that can perform unbiased drug screening and directly measure lifespan and healthspan metrics in whole animals. C. elegans is a powerful model system for this type of drug discovery. Combined with automated data capture and analysis technologies, truly high-throughput longevity drug discovery is possible. In this perspective, we propose the "million-molecule challenge", an effort to quantitatively assess 1,000,000 interventions for longevity within five years. The WormBot-AI, our best-in-class robotics and AI data analysis platform, provides a tool to achieve the million-molecule challenge for pennies per animal tested.
Inhibition of the protein kinase mechanistic target of rapamycin (mTOR) with the Food and Drug Administration (FDA)-approved therapeutic rapamycin promotes health and longevity in diverse model organisms. More recently, specific inhibition of mTORC1 to treat aging-related conditions has become the goal of basic and translational scientists, clinicians and biotechnology companies. Here, we review the effects of rapamycin on the longevity and survival of both wild-type mice and mouse models of human diseases. We discuss recent clinical trials that have explored whether existing mTOR inhibitors can safely prevent, delay or treat multiple diseases of aging. Finally, we discuss how new molecules may provide routes to the safer and more selective inhibition of mTOR complex 1 (mTORC1) in the decade ahead. We conclude by discussing what work remains to be done and the questions that will need to be addressed to make mTOR inhibitors part of the standard of care for diseases of aging.
The racial/ethnic disparities in cancer incidence and outcome are partially due to the inequities in neighborhood advantage. Mounting evidences supported a link between neighborhood deprivation and cancer outcomes including higher mortality. In this review, we discuss some of the findings related to work on area-level neighborhood variables and cancer outcomes, and the potential biological and built/natural environmental mechanisms that might explain this link. Studies have also shown that residents of deprived neighborhoods or of racially or economically segregated neighborhoods have worse health outcomes than residents of more affluent neighborhoods and/or less racially or economically segregated neighborhoods, even after adjusting for the individual-level socioeconomic status. To date, little research has been conducted investigating the biological mediators that may play roles in the associations of neighborhood deprivation and segregation with cancer outcomes. The psychophysiological stress induced by neighborhood disadvantage among people living in these neighborhoods could be a potential underlying biological mechanism. We examined a number of chronic stress-related pathways that may potentially mediate the relationship between area-level neighborhood factors and cancer outcomes, including higher allostatic load, stress hormones, altered epigenome and telomere maintenance and biological aging. In conclusion, the extant evidence supports the notion that neighborhood deprivation and racial segregation have unfavorable impacts on cancer. Understanding how neighborhood factors influence the biological stress response has the potential to inform where and what types of resources are needed within the community to improve cancer outcomes and reduce disparities. More studies are warranted to directly assess the role of biological and social mechanisms in mediating the relationship between neighborhood factors and cancer outcomes.
Aging is driven by hallmarks fulfilling the following three premises: (1) their age-associated manifestation, (2) the acceleration of aging by experimentally accentuating them, and (3) the opportunity to decelerate, stop, or reverse aging by therapeutic interventions on them. We propose the following twelve hallmarks of aging: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis. These hallmarks are interconnected among each other, as well as to the recently proposed hallmarks of health, which include organizational features of spatial compartmentalization, maintenance of homeostasis, and adequate responses to stress.
Both aging and cancer are characterized by a series of partially overlapping "hallmarks" that we subject here to a meta-analysis. Several hallmarks of aging (i.e., genomic instability, epigenetic alterations, chronic inflammation, and dysbiosis) are very similar to specific cancer hallmarks and hence constitute common "meta-hallmarks," while other features of aging (i.e., telomere attrition and stem cell exhaustion) act likely to suppress oncogenesis and hence can be viewed as preponderantly "antagonistic hallmarks." Disabled macroautophagy and cellular senescence are two hallmarks of aging that exert context-dependent oncosuppressive and pro-tumorigenic effects. Similarly, the equivalence or antagonism between aging-associated deregulated nutrient-sensing and cancer-relevant alterations of cellular metabolism is complex. The agonistic and antagonistic relationship between the processes that drive aging and cancer has bearings for the age-related increase and oldest age-related decrease of cancer morbidity and mortality, as well as for the therapeutic management of malignant disease in the elderly.