Premature Physiologic Aging as a Paradigm for Understanding Increased Risk of Adverse Health Across the Lifespan of Survivors of Childhood Cancer

Abstract

The improvement in survival of childhood cancer observed across the past 50 years has resulted in a growing acknowledgment that simply extending the lifespan of survivors is not enough. It is incumbent on both the cancer research and the clinical care communities to also improve the health span of survivors. It is well established that aging adult survivors of childhood cancer are at increased risk of chronic health conditions, relative to the general population. However, as the first generation of survivors age into their 50s and 60s, it has become increasingly evident that this population is also at risk of early onset of physiologic aging. Geriatric measures have uncovered evidence of reduced strength and speed and increased fatigue, all components of frailty, among survivors with a median age of 33 years, which is similar to adults older than 65 years of age in the general population. Furthermore, frailty in survivors independently increased the risk of morbidity and mortality. Although there has been a paucity of research investigating the underlying biologic mechanisms for advanced physiologic age in survivors, results from geriatric populations suggest five biologically plausible mechanisms that may be potentiated by exposure to cancer therapies: increased cellular senescence, reduced telomere length, epigenetic modifications, somatic mutations, and mitochondrial DNA infidelity. There is now a critical need for research to elucidate the biologic mechanisms of premature aging in survivors of childhood cancer. This research could pave the way for new frontiers in the prevention of these life-changing outcomes.

INTRODUCTION

Advances in treatment and supportive care over the past five decades have resulted in improved survival among children diagnosed with malignancies. More than 80% will survive at least 10 years after diagnosis.¹ Unfortunately, a cure is not without life-long consequences, including the early development of adverse health outcomes. Adult survivors of childhood cancer develop chronic health conditions typically seen among persons decades older,² suggesting early onset of physiologic aging and/or frailty. Frailty is a loss of physiologic capacity that interferes with normal function, most commonly described in older adults. In the general population, it identifies individuals highly vulnerable to adverse health outcomes and is a predictor of early mortality.³ In childhood cancer survivors, cancer and treatment exposures may influence the biologic mechanisms of aging, changing the trajectory of normal loss of physiologic capacity, and increasing the risk of frailty (Fig 1).

Fig 1.

Extrapolated figure hypothesizing that molecular integrity and associated physiologic capacity provoked by exposure to chemotherapy and/or radiation may be associated with excess risk and advanced onset of age-related diseases and frailty.

FRAILTY IN ADULT SURVIVORS OF CHILDHOOD CANCER

Data from the St. Jude Lifetime Cohort Study support this hypothesis (Fig 2), documenting frailty among nearly 8% of survivors at a median age of 33 years (range, 18 to 50 years).⁴ This compares with rates among age-matched peers of 0%, and among adults older than 65 years of age of 7.2%.³ Frailty is characterized by three or more of (1) low lean muscle mass, (2) reduced strength, (3) slow walking speed, (4) low energy expenditure, and (5) fatigue.³ The overall loss of physiologic reserve among survivors is substantial; an additional 22.2% of survivors have two of these impairments, and so meet the definition of pre-frail. As is observed in elderly populations, survivors who were frail had a 2.2-fold increased risk of a new-onset chronic condition and a 2.6-fold increased risk of death, independent of treatment exposures and other chronic health conditions.⁴ This is important because reversal and/or prevention of frailty may reduce the burden of disease, improve quality of life, and extend lifespan in this ever-growing population.⁵

Fig 2.

Percentage of survivors in the St. Jude Lifetime Cohort Study (SJLIFE) who meet the criteria for frailty compared with participants in the Cardiovascular Health Study and normal controls. N = 1,922 (50.3% male); mean time since diagnosis, 25.5±7.7 years; mean age at diagnosis, 8.2±5.6 years; 43% leukemia; 33% with cranial radiation exposure.

Components of the frailty phenotype are amenable to intervention in animal models,⁶ and they show promise among the elderly.⁷ However, interventions to remediate or prevent frailty in childhood cancer survivors have not been tested. In addition, although there is some evidence that radiation exposure contributes to the development of frailty among childhood cancer survivors,⁴ those not exposed are also at risk. Associations between chemotherapy and frailty have not been explored fully.⁴ To effectively design interventions, there is a need to gain a better understanding of the mechanisms that result in frail health in childhood cancer survivors. This review describes age-related chronic health conditions, summarizes plausible biologic mechanisms of aging that may be responsible for frailty, and suggests potential interventions that might be tailored to and tested among childhood cancer survivors to prevent or remediate frail health.

AGE-RELATED HEALTH CONDITIONS AMONG CHILDHOOD CANCER SURVIVORS

It is well established that adults who were treated for cancer during childhood are at an elevated risk of early onset of multiple age-related conditions. Data from clinically evaluated participants in the St. Jude Lifetime Cohort indicate that by age 50 years, each survivor, on average, experiences 4.7 grade 3 to 5 chronic conditions.⁸ Condition-specific results from the Childhood Cancer Survivor Study (CCSS) estimate the cumulative incidence of grade 3 to 5 chronic conditions by age 45 years to be 5.3% for coronary artery disease and 4.8% for heart failure.⁹ The incidence is lower in siblings: 0.9% for coronary artery disease and 0.3% for heart failure.⁹ Hypertension requiring medication is prevalent among 14.9% of CCSS cohort members and exponentially escalates the risk of a major cardiac event, including stroke.^9,10 The age-adjusted rate for stroke among childhood cancer survivors is 77 of 100,000 compared with 9.3 of 100,000 person-years among siblings.¹⁰ Incident second neoplasms among childhood cancer survivors are 5.4 times (95% CI, 5.1 times to 5.7 times) higher than expected,¹¹ a median of 17 years after diagnosis. Cataracts are prevalent in > 40% after significant radiotherapy exposure,¹² low bone mineral density in 7.6%,¹³ and metabolic syndrome in nearly a third of survivors¹⁴ at a median age of 32 years. Survivors demonstrate a 1.8-fold (95% CI, 1.4-fold to 2.3-fold) greater risk of developing diabetes mellitus than their siblings.¹⁵ Primary hypogonadism is also prevalent, noted among 8.5% of male and 7.8% of female survivors who are in their 30s.¹³ Cognitive decline, one of the most concerning late effects of childhood cancer, and an age-related phenomenon in the general population, is experienced by survivors, 2% to 13% reporting problems with memory and organization and 22% with task efficiency.¹⁶ Despite reductions in late mortality (≥ 5 years from diagnosis) among survivors treated more recently (15-year cumulative incidence of 10.7% among those treated in the 1970s v 5.8% among those treated in the 1990s), 41% of deaths in the CCSS cohort are attributable to health-related causes rather than to progression or relapse of the primary cancer.¹⁷

Although there is evidence that cancer treatment exposures (Table 1),¹³ and in some cases genetic susceptibility,^18-20 increase the risk of chronic health conditions² and frailty,^21,22 little information is available regarding the underlying biologic and molecular processes driving these outcomes. Although much of what is known about the normal aging process comes from the evaluation of aging in the general and geriatric populations, it is unclear whether these established processes are at work in survivors of childhood cancer. This population was exposed to potentially damaging agents that affected tissue integrity, cellular function, and DNA structure during key developmental periods, which may have prematurely accelerated the molecular processes seen in older adults.

Table 1.

Proportion of Chronic Health Conditions Attributable to Specific Treatment Exposures Among Survivors of Childhood Cancer

MOLECULAR MECHANISMS OF AGING

Aging in the general population is characterized by a loss of physiologic capacity, resulting in impaired function and eventually death (Fig 1). Among childhood cancer survivors, mechanisms responsible for premature loss of physiologic capacity are likely related to treatment-induced damage to normal, nonmalignant cells (neurons, cardiomyocytes, skeletal muscle, and supporting cells) after exposure to radiation and/or chemotherapy. Initial growth arrest at the molecular level may be accompanied by permanent alterations in DNA structure and function, together with interference with normal repair mechanisms at the cellular level, leaving survivors vulnerable to a lifetime of environmental exposures known to further affect the genome. Here we summarize five molecular mechanisms associated with aging in the general population, where evidence suggests a potential contribution to accelerated aging among survivors. These include cellular senescence, telomere attrition, changes in DNA methylation patterns, accumulation of somatic DNA mutations, and loss of mitochondrial fidelity.²³

Cellular Senescence

Cellular senescence (Fig 3), a quiescent state representing the loss of a cell’s ability to replicate or grow, is a fate induced by DNA damage from chemotherapy or radiation, oncogene expression, mutations, repeated cell replication, cell exposure to danger-associated metabolic patterns such as nucleotides or other intracellular constituents, reactive oxygen species, and other damaging metabolites.^24,25 Progression into senescence is mediated by transcription regulator cascades involving the p16^INK4A/retinoblastoma protein, p53/ p21^CIP1, and other factors²⁴ and is accompanied by extensive changes in gene expression, reorganization of chromatin, and ultimately, irreversible replicative arrest, resistance to apoptosis, and sometimes a senescence-associated secretory phenotype (SASP).^24,26-29 The SASP (Fig 2) entails upregulated secretion of hundreds of proteins, including pro-inflammatory cytokines, chemokines, and proteases, among others. Through the SASP, senescence spreads to other cells locally and distantly, contributing to the damaging effects senescent cells have on adjacent tissue and systemic function.^30,31 Senescent cells increase in abundance with age^24,32 and accumulate after DNA-damaging chemotherapy or radiation,³³ in association with frailty,^34,35 and at the sites of pathogenesis of chronic disorders and diseases,³¹ such as bone in osteoporosis,^36,37 vessel walls in arterial sclerosis,³⁸ joints in osteoarthritis,³⁹ the lungs in pulmonary fibrosis,⁴⁰ adipose tissue in diabetes or obesity,^32,41,42 or the liver in hepatic steatosis or cirrhosis.⁴³

Fig 3.

Inducers, mediators, senescent cell anti-apoptotic pathways (SCAPs), the senescence-associated secretory phenotype (SASP), and effects of senescent cells. BCL-2, B-cell lymphoma 2; C/EBPβ, Ccaat/enhancer binding protein beta; Dep, density-enhanced phosphatase; HIF, hypoxia-inducible factor; HSP, heat shock protein; IGF, insulin-like growth factor; IL, interleukin; mTOR, mammalian target of rapamycin; NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells; ROS, reactive oxygen species; TGFβ, transforming growth factor beta.

Many of the inducers and consequences of senescence are relevant to childhood cancer treatment and survivors.⁴⁴ The chemotherapy and radiation administered to treat childhood cancer can induce cellular senescence, as evidenced by increased expression of p16^INK4a in scalp biopsy specimens of children with acute lymphoblastic leukemia exposed to cranial radiation.⁴⁵ In addition, metabolic dysfunction among childhood cancer survivors may be both a consequence of the SASP and a driving factor for additional generation of senescent cells. Muscle weakness, frailty, metabolic and cardiovascular dysfunction, proclivity to develop second cancers, pulmonary fibrosis, an accelerated aging-like state, and early death all have documented associations with or are the consequence of cellular senescence in other populations.^{24,25,31,32,34,38,40,46} However, more evidence is needed to characterize this association among survivors.⁴⁴

Telomeres and Inflammation

Telomeres are nucleoprotein structures capping chromosome ends that protect genome integrity by preventing chromosome end-to-end fusions, nucleolytic processing, and homologous recombination. The length of telomeric DNA, which varies among individuals and cell populations, is heritable and is subject to epigenetic modification.^47-49 Telomere length (TL) shortens with age in replicative tissues lacking telomerase, a specialized reverse transcription that replenishes terminal telomere repeats lost during genome duplication (Fig 4).^50-52 Moreover, TL is strongly correlated across different tissue types from the same individual, with similar rates of attrition over time.⁵³ Once telomeres become critically short, they lose their ability to protect chromosome ends, triggering a DNA damage response and cellular senescence or apoptosis.⁵⁴ Thus, TL predicts cellular replicative capacity.⁵⁵ Mean leukocyte TL (mLTL) shortening is associated with aging-related diseases⁵⁶ including type 2 diabetes,⁵⁷ cardiovascular disease,⁵⁸ dementia,⁵⁹ and increased cancer risk in the general population.^60,61 In addition, shorter mLTL is observed in individuals with impaired grip strength, reduced lean muscle mass, and lower cardiorespiratory capacity,^62-64 all factors characteristic of frailty. Given the accelerated mLTL attrition noted after exposure to chemotherapy and radiation,^65-71 cancer survivors may be at particularly high risk of premature, accelerated aging (Fig 3). In aging populations, loss of TL is likely related to the SASP, because telomere attrition is accompanied by an increase in systemic inflammation,^72,73 characterized by a two- to four-fold increase in the expression of pro-inflammatory cytokines.^74,75 This phenomenon occurs even among healthy individuals lacking comorbidities,⁷⁶ predicting reduced muscle mass and muscle strength and a higher incidence of a frailty phenotype.^77-82 Higher plasma concentrations of interleukin (IL)-6 and tumor necrosis factor-α have been observed in elderly individuals with lower muscle mass, reduced grip strength, and slower walking speed.^83-86 Plasma C-reactive protein, transforming growth factor-β, IL-6, tumor necrosis factor alpha receptor (TNFR) 1, and TNFR2 levels are associated with frailty, in some cases more predictive of frailty than even chronologic age.^87-89 Finally, both shortened TL and systemic inflammation have been shown to predict increased mortality risk in elderly populations.^90-93

Fig 4.

In cells lacking telomerase expression, telomere length shortens with each cell division because of the inability of the lagging strand to replicate terminal nucleotides at the 5′ end. Progressive shortening continues until telomeres become critically short, triggering either cellular senescence or apoptosis.

A few studies have examined the impact of telomere attrition and systemic inflammation on late effects of cancer therapy, and there is some evidence to suggest that these biomarkers are related to therapeutic intensity. For example, the rate of accumulation of comorbidities observed over time in women treated for breast cancer is associated with higher levels of IL-6 and tumor necrosis factor-α, findings that are significantly associated with exposure to multimodal therapy.⁹⁴ Systemic inflammation among adult-diagnosed cancer survivors has also been associated with adverse neurocognitive outcomes and fatigue.^95-97 Similar to studies in adult cancer survivors, female childhood leukemia survivors with higher serum IL-6 and IL-1β levels demonstrate reduced executive function and processing speed.⁹⁸ Shorter mLTL predicts the risk of second cancers,²⁰ and together with elevated plasma inflammatory cytokines, distinguishes survivors of childhood acute leukemia with cranial irradiation from noncancer controls.⁹⁹ In one study specifically designed to investigate frailty, neuroblastoma survivors treated with autologous stem-cell transplant had increased frailty scores compared with age- and sex-matched controls, as well as significantly shorter mLTL and increased C-reactive protein.¹⁰⁰

Methylation

Chromatin has several functions, including control of gene expression and DNA replication. Basic repeating units of chromatin, or nucleosomes, include approximately 150 base pairs of DNA wrapped around eight histone proteins.¹⁰¹ Chromatin structure is regulated by methylation of the 5′-cytosine phosphate guanine-3′ (CpG) dinucleotide, resulting in transcriptional silencing.¹⁰² Although most CpGs in the human genome are methylated, there are large regions of concentrated CpGs (CpG islands) that are hypomethylated. These regions are found in promoter-rich areas and tend to become hypermethylated with age.¹⁰³ The consequences of DNA methylation with age are not completely clear.¹⁰⁴ However, in aging hematopoietic stem cells, regions with altered DNA methylation contribute to dysregulation of gene expression during aging.¹⁰⁵ Although DNA methylation is closely linked to chronologic age,¹⁰⁶ there are deviations from the linear fit of this correlation, indicating that methylation patterns may also reflect biologic age.¹⁰⁴ Methylation is influenced by chronic inflammation¹⁰⁷ and is associated with TL in both adolescents¹⁰⁸ and adults in the general population.¹⁰⁹ Importantly, DNA methylation of blood cells independently predicts all-cause mortality in older adults, even after accounting for traditional risk factors.¹¹⁰ DNA methylation is affected by lifestyle, environmental exposures, and cancer therapies. The acute effects of radiation and some chemotherapy exposures on cancer cells, and in murine models, demonstrate dose-specific differential methylation of genes in pathways consistent with classic biologic responses,^111,112 suggesting that children treated with these agents may experience alterations in DNA methylation. A small study among pediatric medulloblastoma or primitive neuroectodermal tumor survivors indicates that methylation at least influences outcomes, because differential methylation at cg14010619 (PAK4 gene) is associated with ototoxicity.¹¹³

Somatic Mutations

Somatic mutations accumulate throughout life, resulting in tissues that contain a mosaic of cells with different genotypes.¹¹⁴ Mutations occur in all tissues and organs¹¹⁵ but are particularly evident in the aging hematopoietic system and are tied to other biologic markers of aging. For example, recurrent Tet methylcytosine dioxygenase 2 somatic mutations, evident in whole-exome sequencing studies of peripheral blood cells among normal elderly individuals, are associated with alterations in DNA methylation.¹¹⁶ Among older adults, clonal hematopoiesis driver genes are mutated the most frequently and are associated with all-cause mortality and risk of hematologic cancer.^117,118 Recent data indicate that clonal hematopoiesis driver genes may not be responsible for this process in survivors of childhood cancer.¹¹⁹ Nevertheless, because defects in genome maintenance pathways in human progeroid syndromes and in murine models lead to both cancer and the tissue degeneration normally seen in old age,^120,121 we speculate that the accumulation of somatic mutations may explain the increased risk of both cancer and accelerated aging among childhood cancer survivors whose underlying genetics and early life exposures to DNA-damaging agents potentially disrupted genome maintenance pathways. Additional studies exploring this hypothesis in childhood cancer survivors are needed.

Mitochondrial DNA Fidelity

Mitochondrial genomes exhibit higher rates of mutation than do somatic genomes,¹²² rendering mitochondrial DNA (mtDNA) particularly vulnerable to the genotoxic effects of cancer-related therapies. Alkylator-based regimens, for example, are associated with significantly enriched de novo mtDNA mutations in human primary chronic lymphocytic leukemia cells,¹²³ whereas cisplatin preferentially accumulates in mitochondria and structurally disrupts mtDNA synthesis through the formation of mtDNA adducts.^124,125 In addition, acute doxorubicin exposure provokes mtDNA alterations that persist and promote delayed onset of cardiomyopathy in mice.^126,127 In murine models, induced mtDNA pathology is associated with reduced physiologic reserve and signs of premature aging, including kyphosis, loss of bone and muscle mass, weight loss, and anemia (Fig 5).^128,129 Defective mitochondria, and the quality control mechanisms that regulate their accrual, are also tied to the pathobiology of frailty in humans.^130-135 Mitochondrial diseases are characterized by myopathies and neuromuscular disorders,^136,137 and human diseases with muscle-intrinsic pathologies exhibit secondary mitochondrial dysfunction. The accumulation of damaged mitochondria limits the ability of muscle stem cells to effectively sustain or regenerate tissue, resulting in additional loss of muscle, exacerbating existing frail health.^138-143 As with somatic mutations, there is a need for an investigation into the associations between mitochondrial infidelity and accelerated aging in childhood cancer survivors.

Fig 5.

Premature aging phenotype in mitochondrial DNA mutator mice. (A) A representative photograph of 10-month-old mice depicts the smaller size caused by weight loss, alopecia, and graying hair in mice harboring proof-reading defective POLG (Polg^mt/mt). (B) Representative radiographs demonstrate the kyphosis in mutant mice. (C) Representative low-magnification images of hematoxylin and eosin–stained sections highlight the loss of skeletal muscle mass (ie, sarcopenia) in the mutant mice. The mitochondrial DNA mutator mice also develop other age-related disorders, including macrocytic anemia and lymphopenia, osteoporosis, hearing loss, testicular atrophy, and cardiac hypertrophy or dysfunction. Data adapted.^129,130

INTERVENTIONS FOR FRAIL HEALTH

An improved understanding of the molecular mechanisms related to accelerated aging among childhood cancer survivors should facilitate the development and implementation of interventions that target the cells or processes responsible for diminished physiologic reserve. Evidence from other populations and from animal models⁶ indicates that components of the frailty phenotype, and the biomarkers presented here, are responsive to exercise. In the general population, exercise interventions reduce chronic systemic inflammation, mitigate age-related telomere shortening,^144-148 influence methylation patterns,¹⁰⁷ and increase mtDNA abundance in peripheral blood.¹⁴⁹ Although published literature describing effective exercise intervention among children with, or who have survived, cancer is limited, data indicate that survivors can gain lean mass, strength, and walking speed.^40,150-155 However, adherence to exercise is problematic,¹⁵⁶ even in healthy populations. Additional research will require strong behavioral strategies, will need to determine the most appropriate timing of an intervention (during therapy, immediately after a therapy, or years later), and should incorporate outcomes that characterize frailty and that capture the effects of exercise on biomarkers of aging.

Senolytics, soon ready for clinical trials in humans, are pharmaceutical or natural products that selectively eliminate senescent cells.^{25,33,157-160} These agents transiently disable senescent cell anti-apoptotic pathways, resulting in apoptosis of senescent cells, with sparing of nonsenescent cells.^25,159 At least six senescent cell anti-apoptotic pathways have been identified: a dependence receptor/tyrosine kinase pathway, B-cell lymphoma 2–related factors including B-cell lymphoma-xL, a PI3K/AKT/ceramide metabolic network, p53/p21^CIP1/serpine elements, a hypoxia-inducible factor 1α pathway,¹⁵⁹ and a heat shock protein-90 pathway.¹⁶¹ Remarkably, these pathways resemble those that defend cancer cells against apoptosis. In fact, the senolytics identified so far induce cancer cell apoptosis in vitro or in vivo and include dasatinib, quercetin, navitoclax, fisetin, A1331852, and A1155463, among others.^{25,33,158-161} Because senescent cells do not divide and take weeks to months to reaccumulate if the stimuli inducing senescence remain operative, replication-related drug resistance is unlikely to develop. These agents are also attractive because they can be administered intermittently (eg, once a month) because they act by transiently downregulating prosurvival pathways. They do not need to be present continuously in the circulation. Certainly, they may be easier for survivors to adhere to than exercise. In animal models, senolytic drugs have efficacy for treating chronic diseases in animal models, including cardiac,¹⁵⁹ vascular,^38,159 metabolic dysfunction,³² pulmonary fibrosis,^40,162 liver steatosis,⁴³ osteoporosis,^36,163 frailty,¹⁵⁹ and radiation-induced muscle wasting.^159,160 Because childhood cancer survivors have many of the disorders responsive to senolytic drugs, these agents may be effective in alleviating the multimorbidity and accelerated aging phenotypes that occur in these patients.^25,44 Research exploring the use of these agents also must determine the most appropriate timing of their application, either immediately after therapy soon after acute cellular or physiologic injury, or years later when the health conditions typically manifest.

In summary, it is well established that survivors of childhood cancers embark on a lifetime of increased risk of adverse health consequences as a result of cancer and cancer therapy; simultaneously, as they age, many will experience early onset of physiologic frailty, independently increasing the risk of morbidity and mortality. Although there is strong biologic plausibility that age-related molecular pathways identified in the general population may be potentiated by exposure to chemotherapy and radiotherapy during important periods of development, there is a critical need for research in these areas. Better understanding of the underlying biologic mechanisms of premature aging in survivors of childhood cancer could pave the way for new frontiers in the prevention of these life-changing outcomes.

AUTHOR CONTRIBUTIONS

Conception and design: Kirsten K. Ness, James L. Kirkland, Maria Monica Gramatges, Mondira Kundu, Xiujie Li-Harms, Tamar Tchkonia, Saskia Martine Francesca Pluijm, Gregory T. Armstrong

Collection and assembly of data: Kirsten K. Ness, James L. Kirkland, Maria Monica Gramatges, Zhaoming Wang, Mondira Kundu, Xiujie Li-Harms, Jinghui Zhang, Saskia Martine Francesca Pluijm, Gregory T. Armstrong

Data analysis and interpretation: All authors

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Premature Physiologic Aging as a Paradigm for Understanding Increased Risk of Adverse Health Across the Lifespan of Survivors of Childhood Cancer

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.

Kirsten K. Ness

No relationship to disclose

James L. Kirkland

Patents, Royalties, Other Intellectual Property: Unity Biotechnology

Maria Monica Gramatges

Research Funding: Bristol-Myers Squibb

Zhaoming Wang

No relationship to disclose

Mondira Kundu

No relationship to disclose

Kelly McCastlain

No relationship to disclose

Xiujie Li-Harms

No relationship to disclose

Jinghui Zhang

No relationship to disclose

Tamar Tchkonia

Patents, Royalties, Other Intellectual Property: Methods and Compositions for Killing Senescent Cells and for Treating Senescence-Associated Diseases and Disorders (Inst)

Saskia Martine Francesca Pluijm

No relationship to disclose

Gregory T. Armstrong

No relationship to disclose