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 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.

Demographic shifts in the US and worldwide populations are driving large increases in the numbers of adult cancer survivors aged 65 and older, with the greatest growth among older survivors from racially and ethnically minoritized groups (1-7). In parallel, gaps in social determinants of health (SDOH) between minoritized and nonminoritized groups are expected to rise because of continued inequitable societal structures and policies (6,8-12). These differences in social determinants can drive disparities in biological aging, with people from racially and ethnically minoritized populations experiencing accelerated aging (ie, a steeper slope or trajectory of biological aging over time relative to chronological age) more often than individuals from nonminoritized populations (“social determinants of aging”) (6,13). Over time, this accelerated aging is often manifested by disparities in the epidemiology of many aging-related diseases, including cancer (6,13).

Taken together, these trends are expected to increase racial and ethnic disparities among older cancer survivors (6,11,14-21), creating an ethnogeriatric (22) and fiscal crisis in cancer care (23-31). Health systems in many countries are ill prepared to address this crisis because there is limited evidence to guide care that considers the complex, interconnected relationships among these demographic, epidemiological, biological, and sociopolitical forces (6).

We examine this problem through a unique intersectional lens whereby we posit that a portion of the well-established relationships between SDOH and older adult cancer disparities are mediated through differences in damage to biological systems and accelerated biological aging. Further, we postulate that knowledge about aging can enable new mechanism-based pharmaceutical and behavioral interventions (“gerotherapeutics”) (32) that have the potential to reduce cancer disparities between survivors from racially and ethnically minoritized vs nonminoritized groups (6,13,33-36). All persons could potentially benefit from gerotherapeutic approaches, but racially and ethnically minoritized persons have an accelerated rate of aging more often than nonminoritized persons, so we also expect that gerotherapeutics could differentially improve the health and quality of life (QOL) of older racially and ethnically minoritized survivors vs nonminoritized survivors and reduce disparities (6,20,37-53).

There is a large body of knowledge about and many excellent reviews of SDOH (13,54), biological aging processes (13,49,55,56), and cancer disparities (14-17,19,57-60), but none have focused explicitly on the intersection of these topics. In this article, we provide a synthesis of the foundational knowledge that informs our intersectional gerotherapeutic hypothesis. We then discuss methodological considerations for designing future preclinical and clinical studies needed to evaluate the impact of gerotherapeutics on survivorship outcomes among the growing older racially and ethnically minoritized survivor population. We focus on older survivors because they have had the longest time to accumulate the effects of adverse exposures to social determinants of aging and experience cancer disparities, but the issues discussed in this article are also salient to inform future efforts to intervene at younger ages to prevent later-life cancer disparities between racially and ethnically minoritized vs nonminoritized persons.

The intersection of aging, cancer, and cancer disparities

Dynamic, multilevel relationships exist at the intersection of aging, cancer, and cancer disparities (Figure 1). Our central hypothesis is that relationships between SDOH and older adult cancer disparities are mediated through differences in damage to biological systems and biological aging.

Figure 1.

Biological aging mediates the relationship between disparities in social determinants of aging and cancer disparities. Disparities in the balance of adverse vs resilience and buffering social determinants of aging contribute to disparities in rates of biological 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 nonminoritized groups. Acceleration of biological aging can increase the risk, age of onset, aggressiveness, and stage of many adult cancers. There is also a negative feedback loop whereby the cellular damage caused by cancer and its therapies acts as a driver of additional biological aging. Together, these dynamic intersectional forces can contribute to differences in cancer outcomes between minoritized and nonminoritized survivor populations.

Biological aging can be defined as accumulated damage to systems over the course of life, leading to loss of reserve and capacity to respond to challenges; vulnerability to aging-related chronic diseases, including cancer, diabetes, cardiovascular disease, and neurodegenerative disease; functional deterioration, and death (6,20,61-63). This damage can occur through multiple mechanisms. In a recent update of their landmark article on biological aging (49), Lopez-Otin and colleagues added a component to their definition of aging mechanisms: To be considered a hallmark of aging, interventions targeting a specific mechanism should have the ability to slow or reverse aging (55). This new definition is consistent with the “geroscience hypothesis” that gerotherapeutic interventions can slow or mitigate the impact of accumulated damage on biological aging processes, delaying age-related dysfunction and disease (64).

In our framework, as shown in Figure 1, damage to biological systems is influenced by exposures to adverse social determinants of aging, often referred to as the exposome (65-67). These exposures occur more often among racially and ethnically minoritized individuals than among nonminoritized populations, leading to disparities in biological aging (6,13,35,68). This phenomenon is sometimes referred to as “the biology of adversity” or “weathering” (69,70).

Examples of the multilevel adverse social determinants of aging include restricted socioeconomic opportunity, neighborhood deprivation, chronic stress related to adverse childhood events or discrimination, poor working conditions, adverse lifestyle behaviors, exposure to environmental pollution, and experiencing systemic racism (6,13,36,65,71-77). The effects of these adverse experiences on aging can be counterbalanced by buffering factors, including healthy lifestyles, psychological resilience, and social connection (78). The magnitude and frequency of adverse factors tend to outweigh the impact of buffering factors more often in minoritized vs nonminoritized groups, contributing to known disparities in and acceleration of biological aging (6,20,37-53). Differences in biological aging are manifested by disparities in aging-related diseases, including cancer (6,13,67,79-89).

Cancer is unique among diseases of aging (56). Accelerated biological aging can increase the risk, age at onset, aggressiveness, and stage at detection of many adult cancers (6,13). In contrast to most conditions (eg, diabetes, hypertension), where treatment promotes homeostasis and stabilizes the system (eg, lower glucose or blood pressure) and slow biological aging, cancer and its treatments inherently cause damage to biological processes and destabilize the system, causing a negative feedback loop that can drive additional biological aging (20). This overall process contributes to cancer disparities between racially and ethnically minoritized vs nonminoritized groups, including losses in QOL and functional ability, cancer recurrence, and higher cancer-specific and all-cause mortality (6,20,21,38-42,90-107).

Currently, most available data on aging and accelerated aging in cancer survivors are from nonminoritized survivors of childhood and young adult cancers (3,108-110). Although there are some data on aging among adult and older adult survivors (6,105), few studies have characterized the effects of social determinants of aging on biological aging and cancer disparities, and no studies that we are aware of specifically investigate the use of gerotherapeutics to potentially reduce disparities affecting older racially and ethnically minoritized cancer survivors.

In the limited literature to date, older Black breast cancer survivors have been observed in 1 small study to have a statistically significantly older biological age than White survivors based on epigenetic markers, and older biological age was associated with losses of cognitive and physical function (62,111). A report from the CANcer TOxicities cohort in France found associations between multiple socioeconomic factors and long-term QOL but did not assess chronological or biological aging or conduct analysis by racially or ethnically minoritized subgroups (107). In another study, Black adult cancer survivors reported higher deficit accumulation frailty levels than other groups, and higher deficit accumulation was associated with more experiences of discrimination (85,112,113). Interestingly, in an analysis of the US National Health and Nutrition Examination Survey data, Li and colleagues found that adverse lifestyle behaviors, such as smoking, being sedentary, and being obese, were related to cancer mortality, and 26% of this effect was mediated though biomarkers of accelerated biological aging (36). They did not examine these relationships in minoritized vs nonminoritized participants but concluded that geroprotective programs could be useful in caring for older persons (36). Overall, although we cannot change the past adverse life experiences that drive accelerated biological aging, this foundational knowledge provides support to begin testing whether interventions targeting aging mechanisms can reduce cancer disparities among adult and older adult cancer survivors (85).

Targetable aging mechanisms to reduce disparities

The premise of gerotherapeutics is that biological aging can be modulated using behavioral and pharmaceutical interventions that affect a single or multiple hallmarks of aging to improve health (55). We expand this idea to emphasize how information about disparities in social determinants of aging and their effects on biological aging could be used to mitigate or slow accelerated aging and reduce disparities among adult and older adult cancer survivors.

The use of gerotherapeutics to address cancer disparities represents an important opportunity to transform care, especially for racially and ethnically minoritized adult and older adult cancer survivors who may have had accelerated aging before cancer diagnosis due to adverse social determinants of aging, and then were exposed to damaging cytotoxic cancer treatments that can further accelerate aging (32,86,114).

Interventions to slow aging have emerged from animal studies (115,116) and human populations (32,78,116-119), but few studies have addressed issues related to social determinants of aging and racially and ethnically minoritized adult or older adult cancer survivors (120). Here, we focus on 5 aging mechanisms: 1) cellular senescence; 2) DNA repair; and 3) regulation of inflammation, metabolism, and stress responses (Figure 2) (113,121). We chose these mechanisms because 1) it has been established that social determinants of aging affect these mechanisms, 2) pharmacological agents and behavioral interventions have been identified and are being tested as gerotherapeutic agents in animal or human studies targeting these hallmarks, 3) cancer treatment is known to have deleterious effects on these hallmarks, and 4) these hallmarks of aging interact with each other so that gerotherapeutic agents or behavioral interventions targeting 1 mechanism may also provide synergistic effects on other mechanisms (13,20,55,121). Other promising targets include enhancing telomerase to maintain telomere length (122,123); several excellent reviews have provided additional information about other mechanisms that may have potential to reduce disparities (78,119,121,124,125).

Figure 2.

Gerotherapeutic approaches to reducing cancer disparities. Gerotherapeutic behavioral and pharmaceutical intervention approaches can target accelerated aging processes that result from experiencing adverse social determinants of aging and the damaging effects of cancer and cancer therapy. Although all persons could benefit from gerotherapeutic approaches, because racially and ethnically minoritized persons more often experience an accelerated rate of aging than nonminoritized persons, gerotherapeutics could differentially improve the health and quality of life of racially and ethnically minoritized cancer survivors and reduce some of the disparities between minoritized vs nonminoritized survivors.

Cell senescence

Senescence is a process by which damaged cells cease to replicate, resist cell death, and remain metabolically active (126). Accumulation of senescent cells is a key hallmark of many aging-related diseases, with high prevalence in racially and ethnically minoritized groups (53), making it an important gerotherapeutic target (127).

Senescence has pleiotropic effects in the setting of cancer. Early in life it is a stress response that suppresses cancer and can reduce cancer progression in mice (86,114,127-129). Later in life, as organisms age, they accumulate senescent cells that, in turn, can develop a senescence-associated secretory phenotype, which causes tissue necrosis and fibrosis, inflammation, and immune dysfunction in many locations, including adipose tissue (130,131). Thus, senescence cells and their downstream senescence-associated secretory phenotype have both deleterious and beneficial effects, each of which depends on the physiological context (130,132,133). In the setting of cancer therapy, treatment-induced senescence of neoplastic cells is beneficial, limiting tumor replication and spread (134). After the treatment is complete, however, senescent cells can accumulate, increasing senescence-associated secretory phenotype (116).This feedback loop can add to precancer biological aging related to social determinants of aging (135), exacerbating chronic health conditions and lack of recovery from active cancer therapy, widening health and cancer disparities between minoritized and nonminoritized adult and older adult cancer survivors.

These pleiotropic effects of senescence suggest that a “one-two punch” approach might be used in which cancer therapy could be followed by a gerotherapeutic intervention to eliminate senescent cells (113). Eliminating senescent cells in mice reduces senescence-associated secretory phenotype and reverses myelosuppression, cardiac dysfunction, and functional decline (127,134,136).

One can begin to test these approaches by using senolytic drugs—small molecule drugs that eliminate senescent cells—after cancer treatment (113,128). Current candidate senolytic drugs include dasatinib, quercetin, fisetin, genistein, navitoclax, and ruxolitinib. Given the effects of senescence-associated secretory phenotypes on inflammation, there may also be important synergies between senolytics (which ablate senescent cells) and behavioral strategies such as caloric restriction that reduce downstream senescence-associated secretory phenotype markers (lowering inflammation) (137). Drugs that shift aspects of the senescent phenotype, known as senomorphics, may also be beneficial in slowing aging in adult cancer survivors (124). Determining long-term effects of targeting senescence will also be critical because current strategies that target elimination of senescent cells are not specific and carry a theoretical risk of increasing cancer progression because tumor cells can also use antisenescence to escape cytotoxic therapies.

In preclinical studies, several of these agents have been found to prevent, delay, or alleviate several aging-related and senescence-related conditions (138-140). Some are also being tested in cancer survivors vulnerable to accelerated aging after treatment, including childhood cancer survivors (ClinicalTrials.gov identifier: NCT04733534) and older adult breast cancer survivors (ClinicalTrials.gov identifiers: NCT05595499 and NCT06113016) (141). Unfortunately, none of the current trials are testing hypotheses in racially and ethnically minoritized adult or older adult survivors or are powered to test subgroup effects, which will be an important consideration for future studies.

DNA repair

Social determinants of aging are known to affect DNA damage and repair (13,142). DNA damage is induced primarily by exposures to environmental pollutants and ionizing radiation (eg, from outdoor work), which are experienced more often by racially and ethnically minoritized people than by nonminoritized people. Repair of DNA damage is essential to maintain genomic stability. The ability to repair damage diminishes with increasing exposure and age, leading to the accumulation of DNA damage, senescence of damaged cells, and genetic variations that increase cancer risk (143,144). In this setting, a senescence response to DNA damage can be beneficial to the organism by preventing accumulation of cells with cancer-promoting genetic variations, but it can also lead to tissue damage and inflammation through damage induced by the senescence-associated secretory phenotype. Cancer radiation therapy and systemic cytotoxic treatments can cause further DNA damage and lead to additional cellular senescence (145).

DNA damage and repair pathways are likely to contribute to cancer disparities between minoritized and nonminoritized groups, but data are limited data on the direct testing of the effects of interactions of cancer therapy with social determinants of aging on DNA damage (142,146). Mazumdar and colleagues investigated regulation of DNA damage and repair genes in breast tissue from approximately 150 Black women and 700 White women diagnosed with hormone receptor–positive breast cancer (147). They found distinct sets of DNA damage and repair genes upregulated in tumors from Black women but not White women, and these genes were associated with poor survival (147). In another study focused on circulating leukocytes, Divekar and colleagues found differences in DNA damage and repair between Black and White breast cancer survivors following active therapy. The results indicated that the leukocytes from Black (vs White) women had more damage and less DNA repair after in vitro exposure to bleomycin (142). Although both these studies were relatively small, preliminary studies without information about markers of precancer biological age, the results illustrate the concept that the relationship between racial and ethnic group as a proxy for social determinants of aging and disparities in cancer outcomes between racially and ethnically minoritized survivors may be mediated in part through differences in biological aging processes such as DNA damage and repair.

Several potential pharmaceutical intervention strategies that are relevant for the DNA repair process have been tested in preclinical studies, such as the use of blood from young animals to slow aging in older animals, supplementation with nicotinamide adenine dinucleotide–positive precursors and metabolic manipulation (eg, using ketogenic or low-calorie diets) and pharmacological activation of the SIRT6 gene (148-151). These approaches, however, may also have deleterious effects by maintaining cells with poorly repaired DNA sequences. In clinical settings, new cancer therapies directed to DNA damage and repair pathways, such as poly)ADP-ribose) polymerase inhibitors and pembrolizumab, hold the promise of targeting aging, cancer progression, and mortality. Thus, DNA repair is central to aging and interfaces with the other aging mechanisms we have highlighted. Further building the evidence base will be prerequisite, however, to translation and testing of emerging gerotherapeutic interventions targeting DNA damage and repair as a mechanism to reduce cancer disparities.

Inflammatory pathways

Inflammation is an innate immune response to a wide variety of stressors. Chronic inflammation is a common denominator in aging because it can be propagated by interactions between multiple hallmarks of aging (“inflammaging”) (55). Multiple social determinants of aging, including chronic stress resulting from factors such as discrimination, financial adversity, and neighborhood crime—all of which persons from racially and ethnically minoritized groups experience more often than people from nonminoritized groups do—can lead to high levels of chronic inflammation (35,152-156). Chronic inflammation has been linked to risk of developing cancer as well as cognitive decline, loss of physical function, fatigue, response to treatment, and risk of distant metastasis in cancer survivors, although few studies have focused on survivors from minoritized groups (63,157-161). In 1 cross-sectional study by Boyle and colleagues (162) of prostate cancer survivors, 77% of whom were Black men, there were significant associations between neighborhood disadvantage metrics, history of redlining, and racial segregation with tumor RNA expression of proinflammatory genes, although these findings were not linked to biological aging markers or cancer morbidity or mortality.

Several anti-inflammatory drugs, including tumor necrosis factor α and interleukin 1β blockers developed to treat the chronic inflammation seen with autoimmune diseases have been effective in affecting biological aging, including increasing life span in animals (163). In humans, anti-inflammatory drugs have decreased the burden of several aging-related diseases, including prevention of recurrent myocardial infarction and reduced rates of diabetes, hypertension, and lung cancer incidence and mortality (164). Trials of anti-inflammatory pharmaceutical approaches have also been conducted to reduce the morbidity of cancer, and they have used a variety of cancer survivorship endpoints (165-169). None of these studies has specifically focused on racially and ethnically minoritiz

ed adult or older adult populations or included aging-related biomarkers, and results have been inconclusive (170). That said, a relatively new class of antineoplastic drugs that directly target inflammaging, known as immunomodulators, have shown early promise in the treatment of several types of advanced-stage cancers and earlier-stage aggressive tumor types (eg, triple-negative breast cancer) (171). Because these cancers are more prevalent in racially and ethnically minoritized adult and older adult survivors than in other groups, this class of drugs may be a useful gerotherapeutic approach in future efforts to reduce disparities (2,172).

Finally, because several behavioral interventions, such as cognitive behavior therapy for stress reduction, are proven to decrease inflammatory markers in young adult cancer survivors and decrease risk of recurrence (125,173,174), it is possible that combining behavioral and pharmaceutical approaches would be an effective gerotherapeutic strategy.

Metabolic regulation

One prominent characteristic of aging that is affected by social determinants is reduced mitochondrial function leading to energy and metabolic dysfunction (175). When the balance of oxidative stress related to metabolic dysfunction exceeds antioxidant mechanisms, free radicals are generated that can damage DNA and proteins and interact with other hallmarks of aging to accelerate aging and increase disease (55,176,177). Disparities in metabolic dysfunction are reflected in higher rates of diabetes and obesity in minoritized populations, diseases that have been linked to disparities in risk of cancer progression (178-182). Interestingly, the maternal inheritance of the mitochondrial genome and germline variants in mitochondria DNA have been reported as possible drivers of cancer development and aggressiveness in individuals of African ancestry (177). Moreover, failure of mitochondria to adequately supply cells with energy is thought to contribute to common symptoms (175) such as fatigue, frailty, and sarcopenia, and these symptoms are seen more often among racially and ethnically minoritized vs nonminoritized cancer survivors.

Several strategies to improve metabolic regulation and slow aging or even increase the lifespan of mice and humans are emerging (55). Drugs that enhance mitochondrial function, such as L-carnitine, can maintain health in prefrail individuals (183). Metformin, a drug used to treat diabetes, has been observed to decrease mitochondrial aging through effects on adenosine monophosphate–activated protein kinase and mammalian target of rapamycin (mTOR) signaling pathways (184-186). Rapamycin is another drug that has effective antiaging properties through mTOR pathways and has been shown to be protective of neurodegeneration and cancer; it has also increased life expectancy in mice (187-189). Because rapamycin, however, can exacerbate some age-related traits, such as cataracts, longer-term follow-up will be needed to establish safety in humans. Likewise, new drugs that target glucagon receptors and glucagon-like peptide-1 receptors increase fat metabolism and enhance the ability of fatty tissues to rejuvenate their metabolic activity. In addition to weight loss, these drugs can reduce inflammation and improve metabolic regulation, providing theoretical synergies with other gerotherapeutic approaches to reducing cancer disparities among minoritized adult and older adult survivors, although this utility has not been examined, yet (190,191).

Because metabolic aging includes a loss of proper and efficient nutrient sensing, as seen in insulin resistance and glucagon balance, behavioral interventions focused on monitoring glucose and dietary approaches also offer the potential to decelerate aging and reduce all-cause mortality disparities in cancer survivors, especially given the higher rates of obesity, prediabetes, and diabetes in racially and ethnically minoritized cancer survivors (192). Caloric restriction and intermittent fasting offer other behavioral approaches and are thought to operate by suppressing mTOR signaling (193) .Overall, gerotherapeutic interventions targeting metabolism seem promising as an avenue for reducing cancer disparities between racially and ethnically minoritized and nonminoritized adults and older adults.

Stress pathways

Chronic stress is a social determinant of aging through activation of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis, affecting aging through effects on metabolism and cellular damage, telomere erosion, and chronic inflammation (78,153,154,194,195). As noted earlier, some individuals from minoritized groups have more exposure to multiple chronic stressors over their lifetimes than individuals from nonminoritized groups. The increased metabolic activity seen with chronic stress “costs” energy, diminishes metabolic reserve, and may drive obesity and tobacco use (196,197). Stress reduction interventions are thought to have comparable effects on health and aging to commonly prescribed drugs such as statins and antihypertensive drugs (198).

In the setting of cancer survivorship disparities, patients with breast cancer who come from more disadvantaged neighborhoods have been shown to have greater levels of circulating cortisol (199); more aggressive tumors (200,201), including greater tumor expression for inflammatory (activator protein 1, nuclear factor κB); sympathetic nervous system signaling activity (cAMP response element–binding protein) transcripts (201); and shorter cancer survival time (202). In 1 study, crime and safety were cited by breast cancer survivors as sources of adversity, and greater adversity was linked to shorter recurrence-free survival (201). In a case series of breast cancer survivors by Shen and colleagues, greater area deprivation was associated with poor-prognosis tumor features and greater biological aging, as measured by allostatic load and DNA methylation (203).

Behavioral interventions, including cognitive behavioral stress management and treatment of sleep disorders, have been found to be effective in mitigating the stress related to area and personal adversity and are associated with reductions in cortisol and inflammation and lower risk of cancer progression (63,78,125,161,173,204-207). These behavioral interventions also have been noted to have favorable effects on aging biomarkers (78,194). Although cognitive behavior therapy–based stress management interventions are a feasible and efficacious approach to reducing stress and improving QOL in racially minoritized breast cancer survivors (208), the pathway of biological effects has yet to be fully determined (209). In the setting of smoking cessation, Webb-Hooper and colleagues tested the effects of cognitive behavior therapy–based stress management (vs general education) in a diverse sample and found that the intervention was effective among Black, Hispanic, and White smokers (210). They reported, however, that Black smokers were less likely to quit smoking than White smokers and that education and income predicted cessation in Black but not White smokers (210). Webb-Hooper and colleagues concluded that tailored approaches could be useful to change behavior in racially and ethnically minoritized smokers (210,211). Despite these promising examples, there remains a paucity of behavioral studies reporting results for racially and ethnically minoritized adult and older survivors that were specifically designed to test how biological aging pathways may have mediated relationships between social determinants of aging and study outcomes (203,209).

Animal models have used strategies that block sympathetic nervous system signaling, including β-adrenergic antagonists, to prevent or delay cancer progression (212-214), and sympathetic nervous system signaling recently has been related to aging biomarkers (215). Several clinical trials have also found benefit from the use of β-blockers during cancer treatment on short-term and long-term outcomes (213,214,216). Thus, use of β-blockers is a promising area for future investigation, especially given the salience of the effects of chronic stress on aging and disparities (194,201,216), with the added benefit of reducing anxiety symptoms that are prevalent in cancer survivors (216).

Implications for research design

Several unique considerations for designing future studies use the potential of gerotherapeutics to reduce cancer disparities (Box 1).

Equity

It is essential to consider equity when developing new approaches to improve health, which is especially relevant given persistent cancer disparities in the United States and worldwide (2). New technology and therapeutic agents generally have high costs, may not be covered by insurance, require time away from work or caregiving responsibilities, and may be met with skepticism and distrust (217). Therefore, for the potential of gerotherapeutics to be realized as an approach to reduce disparities in aging and their effects on cancer disparities, strategies must consider equitable access to promising approaches, including accessible pricing with no or low co-pays for proven efficacious strategies (218-220). The mode of pharmaceutical intervention administration will also be important to consider in ensuring equitable access (eg, oral vs intravenous administration, length of use, costs). If drugs are effective but expensive or regimens require absence from employment or other responsibilities, they may not reduce disparities.

Box 1.

Questions to consider when designing studies to discover, develop, and test interventions that target aging mechanisms to improve outcomes for older racially and ethnically minoritized cancer survivors

All studies:

Do you have the infrastructure to support studies at the intersection of aging, cancer, and disparities?

Does the intervention address a known aging-related mechanism?

Is there a valid, reproducible measure of the effect of a gerotherapeutic intervention on the specific aging processes being targeted?

Is the animal model appropriate for aging research?

• What are the ages of the animals?

• Do the experiments reasonably represent conditions among older minoritized cancer survivors?

• Do the endpoints include biomarkers and behaviors related to the human outcomes (eg, stress, memory, physical function, quality of life)?

Are investigators from minority populations included in research leadership? Did stakeholders collaborate on study design? Are identity-concordant staff involved in recruitment and retention?

Studies using animal models:

Is the animal model appropriate for aging research?

• What are the ages of the animals?

• Do the experiments reasonably represent conditions among older minoritized cancer survivors?

• Do the endpoints include biomarkers related to the human outcomes?

• Could the model be used to investigate generational effects?

• Will the results generate knowledge that will translate to human studies and inform selection of biomarkers for use in human studies?

Is the intervention safe and effective in animal studies?

• Has the impact of the gerotherapeutic intervention on the pharmacokinetics of the agent and the oncology regimen been conducted?

• Is there the expected effect on biomarkers of the mechanistic pathway?

• Is there the expected effect on behaviors related to aging outcomes?

• Are there effects of behaviors related to the pathway or outcomes

• Is there an effect on distal endpoints (eg, disease-free survival, symptoms)?

• Are there sufficient data to guide power in phase II human trials?

Studies using human participants

Will delivery of the intervention increase equity?

Is the intervention safe in humans?

• Are there preliminary data to support a dosing regimen?

• Do medications for comorbid conditions affect metabolic pathways important to safety or efficacy?

• What toxicities are of concern and can they be mitigated?

Can the intervention be tested among human patients?

• Is the intervention feasible to deliver in clinical or community settings with older patients with cancer?

• What is the optimal timing of delivery relative to cancer diagnosis and treatment?

• Could the intervention be accessible in nonresearch settings?

• Will the dissemination plan increase health equity?

• Is there potential to inform policies and guidelines to increase equity and reduce disparities?

Does the intervention endpoint include patient-reported outcomes?

Does the intervention and study design address the needs of diverse participants?

• Does the study reflect input from diverse stakeholders?

• Are aging-specific issues included (eg, social isolation, retirement, financial security)?

• Is history of social determinants of aging included?

• Are patient-facing materials accessible and inclusive?

• Are any aspects of the intervention of concern for patients with different cultural beliefs?

• Could subpopulation differences in pharmacokinetics due to factors unrelated to the mechanism of interest (eg, minor allele frequencies, food insecurity/malnutrition) affect effects in subgroups?

Is the phase II human trial adequately powered to find meaningful effects in subgroups?

Will the phase II human trial include a sufficiently diverse sample to estimate effects by relevant population subgroups?

Infrastructure

Although researchers from aging and oncology each study disparities, with only 1 exception (National Institute on Aging grant No. R33AG075008), at this time there is no research infrastructure integrating these disciplines. Thus, there is an important need for investment in transdisciplinary research infrastructures to break down silos to study the intersectionality of aging, disparities in aging among racially and ethnically minoritized populations, and cancer disparities. Such infrastructure could bring together scientists to provide the evidence needed to translate gerotherapeutics into clinical care and policies designed to reduce disparities in racially and ethnically minoritized cancer survivors.

Collaboration between the investigators working in a common infrastructure toward harmonization of key constructs could allow analyses of common questions within and across studies to test effects of gerotherapeutic approaches. At present, in the few cohort studies that included a sample of older survivors from minoritized populations, the focus has been on a single racial or ethnic group (112,221-223). This approach has value in providing new data on specific underrepresented groups but may limit comparisons across groups. That said, single-group results could still provide insight into relationships between social determinants of aging and cancer disparities and whether the effects of gerotherapeutics vary differentially across populations.

This type of infrastructure could also increase science, technology, engineering, and medicine workforce diversity and increase the number of National Institutes of Health grantees and academic leaders from racially and ethnically minoritized groups (22,224-233).These objectives are consistently acknowledged by scholars and professional organizations such as the National Institute on Aging and the American Society of Clinical Oncology as an essential component of efforts to decrease the mismatch between the demographics of the increasing older minoritized survivor population and the scientific community and increase representation of older minoritized survivors in research (30,76,234-238).

Recruitment

An obvious design consideration for gerotherapeutic interventions is the need to redress the striking underrepresentation of racially and ethnically minoritized adults and older adults in cancer research. For example, in a review of cognitive aging in cancer survivors, Franco-Rocha and colleagues found that only one-third of studies reported or included survivors from minority groups (239). A 2024 review of the US literature by Gilmore and colleagues examined articles related to cancer disparities in diverse older populations (120). They found that two-thirds of the 59 studies they identified had been published since 2000, with the majority (44 of 59) primarily addressing racially and ethnically minoritized survivors. Unfortunately, most of this research was descriptive and lacked analyses of mechanisms contributing to the reported disparities. Encouragingly, a recent analysis by Schpero and colleagues demonstrated the impact of a structural policy change whereby the number of Black and Hispanic adults participating in cancer clinical trials significantly increased in states that required coverage of routine trial costs under Medicaid but not in states that did not mandate this coverage (240). Comparing data from health-care systems in different countries is also likely to generate new insights into how to improve outcomes for minoritized adults and older adult cancer survivors (241,242).

Underrepresentation of minoritized persons in research is important because it also perpetuates bias and limits researchers’ ability to understand true disparities. In a recent study of the general-population literature, Watkins and colleagues evaluated the characteristics of participants whose data were used to develop epigenetic clocks, a validated tool that captures overall biological aging. They found that racially and ethnically minoritized groups were not included or not reported, introducing potential biases in algorithms used to estimate epigenetic age (243). In this era of growing use of machine learning methods, having unbiased, representative training datasets will be essential to successfully reducing disparities at the intersection of social determinants, aging, and cancer (244,245).

Safety

Another consideration in gerotherapeutic studies targeting reductions in cancer disparities relates to safety. For instance, the opposing goals of cancer treatment (ie, killing cells) and antiaging objectives (ie, maintaining cellular function) implies than any new strategies must be shown to maintain the efficacy of cancer therapy (133). This work includes beginning with animal studies in which gerotherapeutic agents (vs saline control) are administered to animals before or immediately after receipt of common chemotherapy regimens and drug pharmacokinetics are assessed. If feasible, these animal experiments could use animals of comparable age to adult and older adult survivors to maximize clinical translation. Animals could also be followed longitudinally for changes in aging-related markers and behaviors and age at death (246). If animal models demonstrate that gerotherapeutic agents do not adversely affect chemotherapy pharmacokinetics (ie, do not lead to higher or lower levels than established) and maintain the animals’ weight, activity levels, and lifespan at similar levels to the control animals, then phase I and II trials in adult and older adult survivors could begin, first confirming the pharmacokinetics of the gerotherapeutic and oncologic agents, and then proceeding to adverse event assessment, followed by testing for efficacy in clinical populations.

Conducting early-phase human trials will also need explicit consideration of the heterogeneity in health and aging of older adult survivors from different racially and ethnically minoritized groups. For example, dosing of potential gerotherapeutic agents will need to consider multiple comorbidities that may affect drug metabolism. In addition, polypharmacy related to multiple comorbidities may increase the risk of drug interactions. Given known variations in pharmacogenetics that may affect the therapeutic efficacy of gerotherapeutic strategies and underrepresentation of racially and ethnically minoritized groups in whole-genomic sequencing studies (247), sufficient sample sizes will also be needed for analysis of results among minoritized groups.

Measurement

Another key corollary of our focus on aging mechanisms as an approach to reducing disparities among older racially and ethnically minoritized survivors is the need to define surrogate biomarkers for aging biology that can be used to measure the efficacy of gerotherapeutics on disparities in cancer outcomes. There are several excellent reviews of general clinical and biological candidate measures (33,39,61,248-255). In this section, we highlight measurement issues most salient to the intersection of social determinants, aging biology, and cancer disparities, including the potential role of animal models to provide “translationally relevant” data to inform measurement approaches in human studies (246).

Measuring social determinants of aging

At present, although currently recommended clinical assessments of older patients with cancer include review of functioning and disease (256), none focuses on survivorship care or includes guidelines for evaluating social determinants of aging. Understanding past and current social determinants of aging would help clinicians identify cancer survivors at risk of toxicity and poor outcomes, allowing referral for specialty care, rehabilitation, or social work to address needs.

Routine ascertainment of social determinants using a validated, common battery of items (257) and geospatial methods could allow testing of effects of gerotherapeutic approaches on the mediation of specific life experiences and area exposures on biological aging and cancer outcomes. Unfortunately, a recent scoping review by Jayasekara and colleagues found that there were no consistent definitions of domains of social determinants and studies used different measures, data sources, and methods to capture cancer disparities, limiting comparability and conclusions (258). Thus, harmonization will be useful to provide a greater understanding of sources of heterogeneity in aging and cancer disparities among racially and ethnically minoritized adult and older adult cancer survivors.

Measuring biological aging

Several requirements for biomarkers of aging might be useful in testing the effects of gerotherapeutic approaches on health in the setting of reducing cancer disparities among racially and ethnically minoritized adult cancer survivors. These requirements include 1) capacity to reflect the specific processes of aging being targeted, 2) sensitivity to change over the course of an intervention study, 3) reproducibility, and 4) practicality in terms of patient burden and research costs (33). We summarize these requirements in the context of the specific biological aging processes that are the focus of this review; the interested reader is referred to several general overviews for more information on the topic (33,39,61,248-255).

Gonzalez-Gualda and colleagues (135) underscored the complexity of measuring senescence owing to its multiple functions; the interactions of senescence with other aspects of aging; and heterogeneity due to specific antecedent stressors, cell types, and their environment. Senescence is typically measured in cancer research studies using multiple markers, including expression of cell cycle proteins p16^INK4a or p21 (259). There are reports of levels of p16^INK4a expression in the 12 months after breast cancer chemotherapy corresponding to up to 15 years of added aging beyond chronological age, with variability by regimen (259-263). Although p16^INK4a is a nonspecific marker and not yet realistic for testing in clinical practice, the laboratory methods are feasible and appear reliable. Multimarker measurement approaches have also been suggested (135). Before clinical translation, testing of senescence measurement will require validation in studies that include sufficient numbers of samples provided by racially and ethnically minoritized survivors, given the growing recognition of heterogeneity within senescence phenotypes related to varying pathways of stressors that induce cellular senescence (135).

DNA damage can be measured through testing to monitor the removal of DNA damage or to identify the restoration of the original DNA activity. Examples of current biomarkers include testing for micronuclei, host cell reactivation, comet assays, and levels of DNA-repair proteins (264,265). To date, these biomarkers have not been specifically tested in the setting of gerotherapeutic studies or used to examine cancer disparities.

Biomarkers of inflammation are complex to interpret given the rapidly changing and dynamic immune cascade. As a result, panels of markers are usually measured (159). One inflammatory marker, C-reactive protein, captures chronic inflammation levels and is routinely used in clinical practice; it has been linked to physical and cognitive aging in older breast cancer survivors, albeit with limited numbers of minoritized women (158,266).

Metabolic regulation is often measured by glucose and insulin levels as well as metabolic syndrome (defined by abdominal obesity, high blood pressure, impaired fasting glucose levels, high triglyceride levels, and low high-density lipoprotein cholesterol levels). Although these measures are useful for detecting clinically meaningful changes with the use of a gerotherapeutic intervention, they are not likely to be sufficiently sensitive or specific to test impact on specific pathways of metabolic aging. Markers of adenosine monophosphate–activated protein kinase and mTOR signaling pathways may be useful in this regard.

Because stress signaling affects several aging pathways, interventions that specifically target stress reduction will need to consider intermediate markers, such as those using gene expression profiles in circulating immune cells (eg, the conserved transcriptional response to adversity) (267). There is also emerging evidence that markers of pathways involving the receptors of advanced glycation end-products (RAGE) may be useful intermediate biomarkers because RAGE is upstream of proinflammatory and angiogenesis pathways (63,160,268). Testing in animal models of stress, aging, and cancer would be useful for discovering markers with the potential for human translation (246).

Time horizon

Overall survival is especially relevant to adult and older adult survivors, who are more likely to die of other causes than of cancer. Despite the advantage of including overall survival as a study outcome, practical considerations can make long-term follow-up difficult. One approach to this situation is to use common sets of agreed-upon intermediate biomarkers that are related to aging and the functional cancer outcomes of interest (eg, QOL, activities of daily living) (6,85).

Alternative strategies include using animal models among species with genetic overlap with human genes but short lifespans, which enhances the ability to rapidly screen agents (eg, Caenorhabditis elegans) (269). Longitudinal rodent models may also be feasible, but most current animal studies use younger animals; fail to follow younger animals into old age; or cannot fully replicate life stresses, cancer, surgery, and systemic therapies that mimic the exposures experienced by older minority survivors (246).

One useful study design that can capture the full life course is to adapt cancer population simulation models of cancer outcomes in minoritized and nonminoritized groups to integrate biological aging dynamics. Such models could use a plausible range of effects of a particular gerotherapeutic approach and project the impact onto disparities in population QOL or survival. Such hybrid systems biology-population models could also be used to emulate proposed clinical trials to determine sample size, subgroup effects (eg, based on level of comorbidity), and probability of showing proposed effects (270). This approach has been used successfully by the National Cancer Institute–funded Cancer Intervention and Surveillance Modeling Network to address cancer policy (271,272), including a recent monograph about how modeling could be used to guide policies that address systemic racism (58).

The balance of adverse vs positive buffering social determinants experienced over the life course results in differential trajectories of biological aging, with racially and ethnically minoritized persons having an accelerated rate of aging more often than nonminoritized persons. Acceleration of biological aging processes increases the risk and behavior of cancer. Cancer and its therapies create a negative feedback loop that can drive additional aging. Broad societal policy changes are clearly needed to address structural causes of accelerated aging and cancer disparities (201,273). Until then, gerotherapeutic interventions provide a promising opportunity to reduce cancer disparities (274). New transdisciplinary approaches to research will be needed to make this potential a reality. This is an urgent scientific priority given the changing worldwide demographics of the older cancer survivor population and the enormous impact of their care needs on families and health-care systems.

Data availability

No new data were generated or analyzed for this article.

Author contributions

Jeanne S. Mandelblatt, MD (Conceptualization; Investigation; Methodology; Project administration; Resources; Supervision; Writing—original draft; Writing—review & editing); Michael H. Antoni, PhD (Conceptualization; Writing—original draft; Writing—review & editing); Traci N. Bethea, PhD (Conceptualization; Writing—original draft; Writing—review & editing); Steve Cole, PhD (Conceptualization; Writing—original draft; Writing—review & editing); Barry I. Hudson, PhD (Conceptualization; Visualization; Writing—original draft; Writing—review & editing); Frank J. Penedo, PhD (Conceptualization; Writing—original draft; Writing—review & editing); Amelie G. Ramirez, Dr. PH, MPH (Conceptualization; Writing—original draft; Writing—review & editing); G. William Rebeck, PhD (Conceptualization; Writing—original draft; Writing—review & editing); Swarnavo Sarkar, PhD (Conceptualization; Writing—original draft; Writing—review & editing); Ann G. Schwartz, PhD (Conceptualization; Writing—original draft; Writing—review & editing); Erica K. Sloan, PhD (Conceptualization; Writing—original draft; Writing—review & editing); Yun-Ling Zheng, PhD (Conceptualization; Writing—original draft; Writing—review & editing); Judith E. Carroll, PhD (Conceptualization; Investigation; Writing—original draft; Writing—review & editing); Mina S. Sedrak, MD (Investigation; Writing—original draft; Writing—review & editing)

Funding

This work was supported by the National Cancer Institute at the National Institutes of Health grant No. R35CA283926 (J.S.M.). This research was also supported in part by National Cancer Institute at the National Institutes of Health grant No. R01CA129769 and R35CA197289 (J.S.M.), U01CA253911 (J.S.M. and S.S.), K01CA212056 (T.N.B.), R01CA276587 (B.H.), U01CA199240 (A.G.S.), UG3CA260317 (F.J.P. and A.G.R.), R01CA280088 (M.S.S.), R21CA277660 (M.S.S.), and U01CA253911 (J.M. and S.S.) and the National Institute on Aging at the National Institutes of Health grant No. R56AG068086, R01AG082348, R21AG075008, and R33AG075008 (J.E.C. and J.S.M.), U01ES031786 (Y.L.Z.), K76AG074918 (M.S.S.), and R01AG067258 (G.W.R.). E.K.S. was supported in part by grant funding from the National Breast Cancer Foundation (IIRS-20-025), the National Health and Medical Research Council (2020851), and Cancer Council Victoria Grants-in-Aid.

Conflicts of interest

Dr Mandelblatt, who is a Journal deputy editor and the lead author on the manuscript, was not involved in the editorial review or decision to publish the manuscript. Dr Mandelblatt is a co-inventor on a pending invention patent application (PCT/US2022/028741) filed by Georgetown University titled “Use of RAGE inhibitors to Treat Cancer-Related Cognitive Decline” and licensed to Cantex Pharmaceuticals. Dr Mandelblatt has waived her rights and will not receive any renumeration, consideration, or revenue generated from this license or the patents and patent applications licensed thereunder.

Dr Antoni is a paid consultant for Blue Note Therapeutics, a digital health company. He also receives royalties from the American Psychological Association and Oxford University Press for treatment manuals based on cognitive behavioral stress management intervention and from Pearson for the Millon Behavioral Medicine Diagnostic, a personality test.

Dr Hudson is a co-inventor on a pending Canadian patent application (CA3118711A1) filed by the University of Miami titled “Method for Treating Breast Cancer and Chronic Diseases.” Development of this latter invention was supported by the Florida Department of Health, Bankhead-Coley Cancer Biomedical Research Program grant No. 8BC06.

Drs Hudson and Rebeck are co-inventors on a pending invention patent application (PCT/US2022/028741) filed by Georgetown University titled “Use of RAGE Inhibitors to Treat Cancer-Related Cognitive Decline” and licensed to Cantex Pharmaceuticals.

The remaining authors have nothing to disclose.

Acknowledgements

Role of funding agencies: The funding agencies did not have any role in the writing of this manuscript or the decision to submit the manuscript for publication.

We acknowledge anonymous reviewers for constructive and insightful comments on earlier versions of this paper.

Author notes

Judith E. Carroll and Mina S. Sedrak contributed equally to this work as senior authors.