Aging and cancer最新文献

As an oncologist engaged for 45 years in providing ongoing patient care I witnessed a cancer treatment revolution. Multiple options to conventional cytotoxic chemotherapy emerged that led to changing cancer from a rapid fatal disease to a more treatable chronic ailment.  Science was paying off by diminishing the catastrophic effect of cancer for a large number of patients. More people were being cured with less toxic treatments. A significant gain in outcome BUT, my patients were returning with late onset metastases and new primary cancers, this time more difficult to treat and often  associated with the  comorbidities of AGING. This scenario is a global experience. Cancer incidence is increasing in most forms of cancer and mortality rates rising relentlessly with increasing age. The reality is that understanding AGE-related cancer, its evolution, interplay, clinical recognition, and management is underfunded and is an unmet clinical need. As recently as 2015, there has been minimal interactions between the National Cancer Institute and the National Aging Institute to promote research at the interface of aging and cancer, despite the overt links between these processes. Indeed, a major DISPARITY both in research and treating age-related cancer exists.

Yet, ANSWERS are within reach to guide collaborative research to flatten the rising incidence of cancer due to aging. A more holistic view for how aging impacts cancer gaining ground. Aging stem and progenitor cells strive to survive in a changing and often hostile aging stromal environment. This results in somatic variants, epigenetic compensations, loss of gene stability due to DNA damage, and mechanisms to resist exhaustion and death such as reducing immune recognition and hijacking senescence and autophagy  pathways for survival. These changes may be apparent by measurement of clonal progenitor populations with mutations allowing epigenetic driven pathways and cell cycle alterations to emerge to create a survival advantage. Is this privileged and more compensated AGED cell an outlier that is already on a path to cancer clonal evolution and can this be prevented? Clinical and laboratory evidence supports this and  collaborative research is providing models to understand ways to recognize this  transition and identify this threat with precision in the aging cell population. Interventions to diminish age as a risk factor for cancer include education on the importance of “Healthy Aging” and laboratory measurements to distinguish a healthy aged tissue from one with cancerous clonal evolution. Therapeutic interventions to diminish  cancer development in the AGED cell population include early clinical screening, senolytics, specific inhibitors of cell cycle mediators of autophagy, PARP inhibitors, and identifying specific dietary and metabolic dependencies needed to prevent cancer transformation. This type of early screening of AGING stem cells and progenitors and evolving clonal cancer cells

Dr. Samuel Waxman has dedicated his career to the treatment of cancer patients and to cancer research. While he led an extraordinarily successful medical practice for 45 years, he understood very early that knowledge is power and that without research, cancer treatment would remain highly toxic.

His passion for research is best illustrated by the creation of the Samuel Waxman Cancer Research Foundation (SWCRF) in 1976. The SWCRF currently funds a network of 30 researchers across the world and raised over $100 million for cancer research.

To this day, the passion of this remarkable physician-scientist has only become stronger. His most recent goal is to understand the link between cancer and aging. While cancer is known to be an age-related disease, surprisingly, little research focuses on how and why cancer is more frequent in older individuals.

Dr. Waxman has, therefore, not only established collaboration between his foundation and the National Institute of Aging to specifically fund research projects aimed at understanding the link between aging and cancer but also teamed up with Wiley Publishing to launch this new journal in 2020.

In this third edition of Aging and Cancer, three articles from SWCRF investigators were selected to illustrate the range of questions and approaches needed to cover the complexity of the link between aging and cancer.

The first article by our group (Jenkins et al. Are the estrogen receptor and SIRT3 axes of the mitochondrial UPR key regulators of breast cancer sub-type determination according to age? Aging and Cancer, 2021. https://doi.org/10.1002/aac2.12035) focuses on the counterintuitive observation that breast cancer in post-menopausal women, which have much lower levels of circulating estrogen due to the cessation of ovarian function at menopause, tends to develop cancers that show elevated expression of the estrogen receptor.

The second article by Edward Evans and SWCRF investigator James DeGregori (Evans et al. Cells with Cancer-associated Mutations Overtake Our Tissues as We Age. Aging and Cancer, 2021) uses an unbiased approach of a meta-analysis of published sequencing data on normal tissues to determine how many cancer-associated mutations are present in cancer-free individuals with age. They present evidence that these mutations are actually found at high frequency across tissues. This finding immediately raises the question as to why some individuals go on to develop cancer, while others do not.

In direct line with the Evans study, the third article by SWCRF-associated investigator Paolo Boffetta and colleagues (Franchi et al. Developing a multimorbidity prognostic score in elderly patients with solid cancer using administrative databases from Italy. Aging and Cancer, 2021) takes an epidemiological approach to interrogate multiple conditions and their association with Cancer Multimorbidity Score (CMS). Their study suggests that the CMS may be use

The world's population is rapidly aging, and health problems of the elderly are a major focus of the medical system. According to the latest epidemiological report, cancer has surpassed heart disease as the leading cause of death for people over 60 years old. In 2018, a total of 498,963 people over 60 years old died of cancer in the United States. It is estimated that by 2030, 70% of cancers and 85% of cancer-related deaths will occur in the elderly over 65 years old.¹ The elderly population will undoubtedly comprise a major part of cancer cases in the future. Previous research has revealed the intimate association between aging and cancer.^1-3 The development of cancer is a time-dependent process with increased incidence in later phases of life. Environmental carcinogens are more likely to impact older tissues and carcinogenesis is also promoted by the aging-related changes in body environments like chronic inflammation and immunosenescence. These factors contribute to the increased incidence of cancers with age. Currently, more than 50% of newly diagnosed cancer patients are over 60 years old and about one-third older than 70 years. Take lung cancer and pancreatic cancer for example—the incidence of lung cancer is only 0.7% in patients younger than 60 years old, while the incidence is up to 14.3% in those over 60 years old. Among newly diagnosed pancreatic cancer patients, only 13% of all pancreatic cancer cases were diagnosed below the age of 60.⁴

In clinical practice, surgery and chemotherapy still remain the primary options for most cancers, and a comprehensive assessment for physical condition is required before decision making to determine whether the patient is sufficiently tolerant of treatment.⁵ The treatment strategies for elderly cancer patients are less aggressive based on various considerations, medical and socioeconomic, thereby leading to detrimental effects on life expectancy for these patients. Although elderly patients often present with additional chronic diseases (e.g., heart diseases, chronic lower respiratory diseases, and cerebrovascular diseases), and decline of multiple organ functions, aging is still a highly individualized process that cannot be evaluated merely by chronological age.⁶ Comprehensive geriatric assessment (CGA) is a concept proposed in geriatric oncology to serve as a multidimensional tool for integrating therapeutic decision making in older adults based on their biological age. Prior studies have confirmed the capability of CGA to predict the risk of morbidity and mortality among elderly cancer patients, suggesting that evaluation systems of high sensitivity and specificity for treatment strategies of old patients with cancer are clearly needed.⁷

Anesthesia and surgery are both challenging for older patients requiring tumor resections. Many elderly

Cardiovascular diseases (CVD) are the leading cause of death worldwide, and age is by far the greatest risk factor for developing CVD. Vascular dysfunction, including endothelial dysfunction and arterial stiffening, is responsible for much of the increase in CVD risk with aging. A key mechanism involved in vascular dysfunction with aging is oxidative stress, which reduces the bioavailability of nitric oxide (NO) and induces adverse changes to the extracellular matrix of the arterial wall (e.g., elastin fragmentation/degradation, collagen deposition) and an increase in advanced glycation end products, which form crosslinks in arterial wall structural proteins. Although vascular dysfunction and CVD are most prevalent in older adults, several conditions can “accelerate” these events at any age. One such factor is chemotherapy with anthracyclines, such as doxorubicin (DOXO), to combat common forms of cancer. Children, adolescents, and young adults treated with these chemotherapeutic agents demonstrate impaired vascular function and an increased risk of future CVD development compared with healthy age-matched controls. Anthracycline treatment also worsens vascular dysfunction in midlife (50–64 years of age) and older (65 and older) adults such that endothelial dysfunction and arterial stiffness are greater compared to age-matched controls. Collectively, these observations indicate that use of anthracycline chemotherapeutic agents induces a vascular aging-like phenotype and that the latter contributes to premature CVD in cancer survivors exposed to these agents. Here, we review the existing literature supporting these ideas, discuss potential mechanisms as well as interventions that may protect arteries from these adverse effects, identify research gaps, and make recommendations for future research.

The immune system of elderly individuals behaves differently from young adults, leading to a general assumption that the decline of immune system function increases the susceptibility to infectious and noninfectious diseases. This age-related internal immune function failure, termed "immune senescence," contributes to the increment of morbidity and mortality associated with diseases in elderly populations. Cord blood is considered as a source of “young” immune cells for anti-infectious immunity and adoptive cancer immunotherapy. In this review, we describe immune aging and the application of cord blood for replenishing aging immune cells against neoplastic diseases.

Skeletal muscle (muscle) is essential for physical health and for metabolic integrity, with sarcopenia (progressive muscle mass loss and weakness), a precursor of aging and chronic disease. Loss of lean mass and muscle quality (force generation per unit of muscle) in the general population are associated with fatigue, weakness, and slowed walking speed, eventually interfering with the ability to maintain physical independence, and impacting participation in social roles and quality of life. Muscle mass and strength impairments are also documented during childhood cancer treatment, which often persist into adult survivorship, and contribute to an aging phenotype in this vulnerable population. Although several treatment exposures appear to confer increased risk for loss of mass and strength that persists after therapy, the pathophysiology responsible for poor muscle quantity and quality is not well understood in the childhood cancer survivor population. This is partly due to limited access to both pediatric and adult survivor muscle tissue samples, and to difficulties surrounding noninvasive investigative approaches for muscle assessment. Because muscle accounts for just under half of the body's mass and is essential for movement, metabolism, and metabolic health, understanding mechanisms of injury responsible for both initial and persistent dysfunction is important and will provide a foundation for intervention. The purpose of this review is to provide an overview of the available evidence describing associations between childhood cancer, its treatment, and muscle outcomes, identifying gaps in current knowledge.

The treatment of older persons with cancer is fraught by a delicate balance of targeting the disease while avoiding treatment-related complications. “Personalized,” or “precision” medicine approaches can ease this problem through more efficacious and less toxic treatments. Multiple myeloma epitomizes the struggle to balance treatment options and their complications, for it is an incurable disease afflicting a predominantly aged population, and treatment is administered on a continuous schedule with little or no breaks. Over the last two decades, advances in drug development have improved outcomes for younger, fit patients, but older, frail patients have not realized the same benefit. This could be related to the benefits of three drug combinations, when frail patients can often tolerate only two drugs at a time. In myeloma, personalized approaches have lagged behind some other malignancies due to its genetic complexity and a paucity of abnormalities with associated targeted therapies. In contrast, the disease is managed with an array of drugs that target phenotypic characteristics common in malignant plasma cells. To address the unmet need for personalized medicine in myeloma, we developed a functional approach by profiling the sensitivity of patients’ myeloma to clinically available drugs. Through this, we observed that receiving at least two effective drugs portended better outcomes, leaving those patients who can only tolerate two drug regimens without room for error. We now describe a frail patient's case and their drug sensitivity profile to illustrate how personalized treatment could have led to an improved disease course. Personalized treatment could provide the greatest survival improvements to older adults with cancers, such as multiple myeloma, through avoiding undertreatment, limiting attrition through subsequent lines of therapy, reducing exposure to ineffective drugs and streamlining the management of relapses. Exploring these avenues is imperative to closing the gap of cancer-related mortality in older and frail persons.