Introduction: Beyond “Aging → Cancer” to “Cancer → Aging”
In the Introductory and earlier Expert Series articles, we mainly focused on the direction:
- Aging increases the risk of cancer
- Tissue- and genotype-specific aging patterns shape where and when cancers arise
In other words, the emphasis was on “aging → cancer.”
However, emerging evidence suggests that the reverse direction also matters:
- Cancers can accelerate aging of the immune system and other organs
- Cancer therapies (chemotherapy, radiation, stem cell transplantation, etc.) can leave long-term marks on systemic aging
In this article, we will focus on three aspects:
- How hematologic malignancies (e.g., lymphomas) can accelerate aging signatures in immune cells and tissues
- How solid tumors may reshape systemic metabolism, inflammation, and hormones in ways that promote aging
- How cancer treatment itself induces “therapy-induced aging” and influences long-term health
By doing so, we aim to clarify the “vicious cycle” between cancer and aging from both mechanistic and clinical perspectives.
Reframing Cancer as an Inducer of Immune and Tissue Aging
Malignant Lymphoma and Systemic Aging Signatures
In hematologic malignancies such as malignant lymphoma, tumor cells proliferate in lymph nodes and bone marrow, interacting intensively with immune and stromal cells. Recent studies have reported that:
- T cells and bone marrow–derived cells in lymphoma patients exhibit stronger “aging signatures” than those in age-matched healthy individuals
- These aging signatures correlate with tumor burden and may partially improve when tumors respond to therapy
These observations suggest a causal relationship:
- The tumor itself accelerates aging of immune cells and surrounding tissues
Tumor Microenvironment (TME) and Propagation of Local Aging
The tumor microenvironment (TME) around a cancer includes blood vessels, fibroblasts, immune cells, adipocytes, and other components. Within this compartment, we often see:
- Chronic inflammation
- Hypoxia and nutrient stress
- Persistent secretion of immunosuppressive cytokines such as TGF-β and IL-10
Cells residing in such environments may adopt features similar to senescent cells, including permanent cell-cycle arrest and pro-inflammatory secretory profiles. Senescent and chronically activated cells in the TME may:
- Stabilize a local environment that favors tumor growth and immune evasion
- Release cytokines, chemokines, and extracellular vesicles that transmit aging and inflammatory signals systemically
In this way, “cancer-associated local aging” can, in principle, contribute to the acceleration of systemic aging.
The Immune Perspective: When Cancer Drives Immune Aging
1) T Cell Exhaustion and Its Overlap with Aging
Chronic exposure to tumor antigens leads to T cell exhaustion, a state characterized by:
- Reduced effector function
- High expression of inhibitory receptors (e.g., PD-1)
- Impaired proliferation
Intriguingly, exhausted T cells share several features with “aged” T cells observed in older individuals. When tumors persist for prolonged periods:
- Even relatively young patients may accumulate exhausted or senescent-like T cell subsets
This may result in:
- Further weakening of anti-tumor immunity
- Reduced responses to infections and vaccines—hallmarks of accelerated immune aging
2) Effects on Hematopoietic Stem Cells and the Bone Marrow Niche
Both hematologic and some solid tumors can perturb the bone marrow niche. Chronic inflammatory cytokines and tumor-derived factors may:
- Skew differentiation of hematopoietic stem cells (HSCs)
- Promote clonal hematopoiesis with expansion of specific clones
Over time, this can contribute to:
- Increased risk of secondary hematologic malignancies
- Features of immune aging and altered blood cell composition
The longer the tumor persists, the more opportunity there is for such “bone marrow–level aging” to accumulate.
Solid Tumors and Systemic Aging: Metabolism, Inflammation, Hormones
1) Cancer Cachexia: A Rapidly Induced Aging Phenotype
In advanced cancer, many patients develop cachexia—a syndrome characterized by weight loss, muscle wasting, and metabolic disturbances. Tumor-derived factors and chronic inflammation drive:
- Increased proteolysis in skeletal muscle
- Abnormal breakdown of adipose tissue
- Anorexia and energy imbalance
Clinically, cachexia resembles age-related sarcopenia and frailty. Patients who experience cachexia often have:
- Worsened functional status and higher mortality
In this sense, cancer can compress “years’ worth of aging” into a short interval in muscular and metabolic systems.
2) Hormonal Changes and Tissue Aging
Hormone-dependent tumors (e.g., breast and prostate cancers) and tumors of endocrine organs (adrenal, thyroid, etc.) can profoundly alter systemic hormone balance and downstream tissue homeostasis. For example:
- Hormone therapies and ovarian suppression in breast cancer can accelerate bone loss and increase cardiovascular risk
Thus, cancer and its therapy may induce an “accelerated menopause” or “accelerated aging” in specific systems, even when chronological age is not advanced.
Therapy-Induced Aging: A Double-Edged Sword of Cancer Treatment
1) DNA-Damaging Therapies and Accumulation of Senescent Cells
Many chemotherapies and radiotherapies exert their anti-tumor effects by inducing DNA damage. Normal cells are inevitably affected, leading to:
- Cell death in some populations
- Entry into a senescent state in others
Senescent cells:
- Do not proliferate but secrete pro-inflammatory cytokines, proteases, and other factors (the SASP, or senescence-associated secretory phenotype)
Over the long term, this may contribute to:
- Atherosclerosis, fibrosis, metabolic disease, and secondary cancer risk
In some cancer survivors, biologic age estimated by epigenetic clocks appears higher than that of age-matched controls, suggesting that therapy may temporarily or persistently accelerate aging trajectories.
2) Hematopoietic Stem Cell Transplantation and Early-Onset Aging
Autologous or allogeneic hematopoietic stem cell transplantation (HSCT) offers curative potential for many hematologic malignancies, but it involves:
- Intensive conditioning with high-dose chemotherapy and/or total body irradiation
- Prolonged immunosuppression and chronic graft-versus-host disease (GVHD) in the allogeneic setting
Long-term survivors of HSCT exhibit elevated rates of:
- Cardiovascular disease, endocrine abnormalities, second cancers, and cognitive changes
These patterns resemble an “early-onset aging” phenotype and represent a textbook example of therapy-induced aging.
3) Immune Checkpoint Inhibitors: Rejuvenation and Injury
Immune checkpoint inhibitors can, in a sense, “rejuvenate” exhausted or aged immune responses against tumors. At the same time, they may cause immune-related adverse events (irAEs) such as:
- Myocarditis, pneumonitis, and endocrine dysfunction
These events can inflict acute damage that has long-term consequences for organ function, potentially contributing to premature aging of specific systems. Balancing the benefits of immune rejuvenation against the risk of accelerated organ damage remains an active area of research.
Breaking the Vicious Cycle of Cancer and Aging
1) Bidirectional Feedback Between Cancer and Aging
We now see that:
- Aging increases cancer risk (“aging → cancer”)
- Cancer and its treatments can accelerate aging (“cancer → aging”)
This bidirectional feedback can be particularly harmful in older or frail patients, in whom reserve is limited and additional aging burden translates directly into reduced healthy life expectancy.
2) The Role of Supportive Care, Rehabilitation, and Lifestyle Interventions
Cancer treatment planning should consider not only tumor control but also:
- How to minimize the treatment-induced aging burden
Practical implications include:
- Integrating nutritional support, exercise, and rehabilitation from early in the treatment course
- Monitoring cardiovascular, metabolic, bone, and cognitive health as part of standard follow-up
- Engaging geriatricians, rehabilitation specialists, and mental health professionals in multidisciplinary care
3) Toward “Aging-Informed Oncology”
In the future, aging metrics such as epigenetic clocks and immune aging markers might be used to:
- Assess baseline aging profiles before treatment and tailor therapy intensity and supportive care accordingly
- Monitor changes in aging markers during and after treatment as early indicators of long-term risk
This vision of “aging-informed oncology” is appealing but requires robust validation, standardized assays, and careful ethical frameworks.
Limitations and Open Questions
How Much and How Reversibly Does Cancer Accelerate Aging?
Important questions remain:
- How large is the impact of different cancers and therapies on aging markers?
- To what extent are these effects reversible with time, remission, or interventions?
The answers likely depend on tumor type, stage, treatment regimen, and patient characteristics, and may differ between organ systems.
Targeting Aging Itself: Opportunities and Risks
Senolytics (drugs that selectively eliminate senescent cells) and agents that modulate the SASP are being investigated for age-related diseases. In oncology, potential applications include:
- Mitigating therapy-induced aging by clearing treatment-induced senescent cells
- Remodeling the tumor-associated senescent microenvironment to enhance therapy
However, these strategies must be balanced against risks such as:
- Eliminating cells needed for tissue repair and remodeling
- Disrupting beneficial tumor-suppressive forms of cellular senescence
Careful preclinical and clinical studies will be essential before such approaches can be integrated safely into cancer care.
Conclusion: Viewing Cancer and Aging as a Bidirectional Network
In this third Expert Series article, we have explored how:
- Hematologic malignancies can accelerate aging signatures in immune cells and tissues
- Solid tumors may drive systemic aging via cachexia, inflammation, and hormonal changes
- Cancer therapies contribute to therapy-induced aging, with long-term implications for survivors
These insights reinforce the idea that aging and cancer form a bidirectional network rather than a one-way street. The challenge ahead is to identify:
- Where in this network we can intervene to maximize both tumor control and healthy life expectancy
In upcoming parts of the Expert Series, we will shift our focus to more specific themes, such as:
- Reproductive aging and women’s cancers of the ovary, uterus, and breast
- Challenges in modeling aging and cancer in experimental systems and translating findings to humans
My Thoughts
Reframing the aging–cancer relationship as bidirectional helps make sense of many clinical observations: the patient who seems to age a decade in a few months of living with advanced cancer; the survivor whose tumor is cured but who faces an accumulation of cardiovascular, metabolic, and cognitive problems in subsequent years.
At the same time, telling patients that “cancer accelerates aging” can be deeply distressing. The key is not whether we state this explicitly, but how we translate the underlying understanding into concrete support: “Because of this risk, we will protect your muscles and heart as much as possible,” or “We will monitor and address long-term complications early.” In other words, the point is to use knowledge about aging not as a sentence, but as a basis for co-designing care.
Research on senolytics, aging biomarkers, and advanced imaging often captures headlines. Yet the real-world interplay between cancer and aging is complex, multi-layered, and deeply individual. No single biomarker or drug will fully resolve this complexity. The most important task may be deciding where to draw the line between what we quantify and what we address through conversation, judgment, and shared decision-making. In that sense, the study of cancer and aging is not just a scientific frontier, but also an ethical and human one.
This article has been edited by the Morningglorysciences team.
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