Breast cancer survivors face accelerated aging tied to tumors and treatment

By Dr. Liji Thomas, MDReviewed by Lily Ramsey, LLMMar 20 2025

Many breast cancer (BC) survivors experience accelerated aging, potentially due to the cancer itself or the effects of various treatments.

A recent study in Aging explored the relationship between Phenotypic Age Acceleration (PAA) and BC characteristics and treatments.

Study: Accelerated aging associated with cancer characteristics and treatments among breast cancer survivors. Image Credit: Ground Picture/Shutterstock.com

Introduction

Breast cancer is the most common cancer among women worldwide. However, early diagnosis and treatment significantly improve survival rates, with five- and ten-year survival rates at 91% and 85%, respectively.

As a result, millions of women are living as BC survivors, including four million in the United States alone.

Despite their extended lifespan, BC survivors often face faster cognitive decline and physical frailty compared to women without cancer. The study utilized a relatively new measure of aging—Phenotypic Age Acceleration (PAA)—to evaluate biological aging in BC survivors.

PAA is calculated by combining chronological age (CA) with C-reactive protein (CRP, an inflammatory marker) and eight routine blood biomarkers, providing a cost-effective and accessible way to assess aging and predict mortality risk.

Study participants

The study included 1,264 BC patients and 429 cancer-free controls. BC patients were, on average, five years older than controls and had double the mortality rate (8% vs. 4%) over a median follow-up period of nine years.

At diagnosis, 68% of patients were in stage I or II, while 17% had stage III/IV disease. High-grade tumors were present in 35% of cases, with intermediate-grade tumors in 39%. Nearly half (45%) of patients had hormone receptor-positive but HER2-negative (HR+/HER2-) BC, while 13% had HER2-positive BC and 14% had triple-negative BC (TNBC).

Treatment varied widely. Surgery was the most common intervention, performed in nearly 90% of cases. Chemotherapy was used in 60% of patients, while 51% received radiation therapy and 66% underwent hormone therapy.

Targeted therapy was administered to 17% of patients, but only 3% received immunotherapy. Over the follow-up period, 2% developed a second BC, and 20% experienced metastasis or recurrence.

Study findings

BC patients exhibited higher PAA than controls. At diagnosis, their phenotypic age (PA) exceeded their chronological age (CA) by an average of four years. This gap narrowed to two years at one-year post-diagnosis and one year at ten years, with no significant differences at two or five years.

The degree of PAA varied based on several factors. Patients diagnosed at age 65 or older were initially phenotypically younger than their CA, but over time, they aged faster, surpassing their CA by 1.5 years at two, five, and ten years.

Those with stage III/IV BC exhibited a five-year PAA at diagnosis, which persisted for ten years. High-grade tumors were linked to sustained accelerated aging, peaking at a three-year difference at one year and remaining two years higher at year ten.

Cancer subtypes also influence aging patterns. HER2+ patients aged faster than HR+/HER2- patients, with a PAA of two years at year one and 1.5 years at year five.

TNBC patients experienced an accelerated aging rate of 3.5 years at year one and two years at year two. However, by year ten, this trend reversed, and their PA was two years lower than their CA.

Treatment impact on aging

Different treatment modalities had varying effects on aging. Surgery appeared to have a protective effect, with patients showing a phenotypic age seven years younger than their CA at year ten. Radiation therapy alone resulted in a two-year reduction. When both were used together, the impact was similar to that of surgery alone.

Chemotherapy and targeted therapy did not significantly impact PAA when administered alone. However, combination regimens that included chemotherapy led to accelerated aging by four years at one-year post-diagnosis.

Patients who received hormone therapy—whether alone or alongside chemotherapy and targeted therapy—aged nearly three years faster than their CA at both one and ten years.

Among chemotherapy agents, alkylating agents and anthracyclines initially increased PAA by two years at year one. However, this effect reversed over time, leading to a two- to 2.5-year reduction in PA at years five and ten.

In contrast, antimetabolites, selective estrogen receptor modulators (SERMs), and aromatase inhibitors (AIs) initially reduced PA by a year at year two.

However, antimetabolites ultimately accelerated aging by seven years at year ten, while AIs added two years to the CA at the same time point. These findings suggest that hormone therapy may contribute to faster aging overall.

Mechanisms of accelerated aging

Accelerated aging in BC survivors may result from multiple factors. Cytotoxic chemotherapy can induce cellular senescence, telomere shortening, chronic inflammation, mitochondrial dysfunction, genomic instability, and epigenetic alterations. The study indicates that these effects may persist even ten years after diagnosis.

Hormone therapy may also play a role by disrupting normal hormonal adaptation, genomic stability, and mitochondrial function, leading to stem cell exhaustion and increased biological aging.

Conclusions

“This study provides evidence of accelerated aging among BC survivors and identifies high-risk populations based on tumor characteristics and treatments.” Notably, this is the first study to apply PAA based on biochemical markers rather than epigenetic parameters in BC survivors.

However, the findings must be interpreted cautiously due to selection and survival biases. Patients with high-grade tumors or aggressive treatments may have higher PAA but also higher rates of recurrence or death, potentially skewing results.

Additionally, tumor characteristics primarily influence aging at diagnosis rather than during follow-up.

Further research is needed to explore how demographic and lifestyle factors interact with aging-related outcomes in BC survivors, particularly with modern treatment regimens. These insights could help improve long-term care and quality of life for survivors.