AGE/DOSE
Aging & Longevity

Mayo Clinic Study Strongly Associates Senescent Cells with Shortened Lifespan

High blood markers related to senescent “aged” cells are associated with an increased risk of mortality in older adults.

By Griffin Dean

Key Points: 

  • Senescent cell biomarkers predict the likelihood of mortality with greater accuracy than traditional risk factors, such as old age, sex, and race.  
  • Many of these biomarkers are associated with chronic diseases that also increase the risk of mortality, including heart disease and cancer. 

Senescent cell build up is believed to drive the aging process, largely by secreting molecules known as SASP (senescence-associated secretory phenotype) factors. However, there are few human studies supporting this notion. Now, in a study published in Aging Cell, Mayo Clinic researchers have found that SASP factors are associated with an increased risk of mortality in older individuals, lending credence to the “senescence drives aging” hypothesis. 

Cellular Senescence Increases Risk of Death  

The study included 1,923 individuals above the age of 65 who were followed for about 6 years. Of the participants, 68% were free of chronic conditions while the rest faced only one condition, such as arthritis or a history of cancer. By the end of the study, 293 participants passed away, allowing the researchers to determine factors associated with increased mortality risk. 

Previously known risk factors for increased mortality, including advanced age, being male, and being categorized as non-white, were confirmed and factored into the analysis. Subsequently, it was found that 14 senescence biomarkers, measured from blood samples, were associated with increased risk of death. The markers with the strongest association are called GDF15, VEGF, PARC, MMP2, and RAGE. 

“These results suggest that blood-based biomarkers of cellular senescence in older adults may be informative predictors of biological age and clinically important health outcomes, including death,” said the authors.

(St. Sauver et al., 2023 | Aging Cell) Senescence Biomarkers Increase Mortality Risk. Increased levels of senescent markers GDF15, VEGF, PARC, and MMP2 are associated with increased risk of death (HR for death), while lower levels of RAGE are associated with increased risk of death. Older age, being a male, and non-white race also increase the risk of death, while having 1 chronic condition (1 Dz) decreases risk of death.

The 14 senescence biomarkers found to increase the probability of death are called SASP factors. SASP factors are secreted by senescent cells from different organs and travel throughout the body via the bloodstream. In this way, each SASP factor could damage other organs, leading to chronic disease. 

Of the SASP factors measured, the results showed that GDF15 appeared to have the highest predictive power for mortality. Higher GDF15 levels have previously been observed in individuals with heart disease and cancer, suggesting GDF15 could promote these chronic diseases. 

Similarly, the other four SASP factors most strongly associated with increased mortality risk, VEGF, PARC, MMP2, and RAGE have previously been linked to chronic diseases like heart disease, cancer, and lung disease, along with increased risk of death from these diseases. It follows that these SASP factors may be capable of promoting life-shortening chronic diseases. The authors conclude: 

“In summary, biomarkers of cellular senescence improved prediction of mortality beyond traditional demographic and clinical characteristics, suggesting that circulating concentrations of these proteins may reflect a fundamental mechanism of aging that ultimately leads to death.”

Are Senolytics the Key to Avoiding Mortality Risk?

Senolytics are compounds that selectively eliminate senescent cells, which evade cell death and accumulate with aging. Moreover, by removing senescent cells, the concentration of SASP factors in the blood may be reduced. In this way, senolytic therapy could lead to a longer lifespan by counteracting chronic diseases like heart disease and cancer by alleviating senescence. 

Indeed, studies have shown that the senolytic combo dasatinib and quercetin can restore heart function in a heart attack model, suggesting that senolytic therapy can combat heart disease. Additionally, the senolytic ABT-737 has been shown to halt pancreatic cancer development in mice. While human studies are necessary, these studies support the notion that senolytic compounds could counteract the same diseases that SASP factors seem to promote. 

Source

St. Sauver, J. L., Weston, S. A., Atkinson, E. J., Mc Gree, M. E., Mielke, M. M., White, T. A., Heeren, A. A., Olson, J. E., Rocca, W. A., Palmer, A. K., Cummings, S. R., Fielding, R. A., Bielinski, S. J., & LeBrasseur, N. K. Biomarkers of cellular senescence and risk of death in humans. Aging Cell, e14006. https://doi.org/10.1111/acel.14006

References

Salerno N, Marino F, Scalise M, Salerno L, Molinaro C, Filardo A, Chiefalo A, Panuccio G, De Angelis A, Urbanek K, Torella D, Cianflone E. Pharmacological clearance of senescent cells improves cardiac remodeling and function after myocardial infarction in female aged mice. Mech Ageing Dev. 2022 Dec;208:111740. doi: 10.1016/j.mad.2022.111740. Epub 2022 Sep 20. PMID: 36150603.

Kolodkin-Gal D, Roitman L, Ovadya Y, Azazmeh N, Assouline B, Schlesinger Y, Kalifa R, Horwitz S, Khalatnik Y, Hochner-Ger A, Imam A, Demma JA, Winter E, Benyamini H, Elgavish S, Khatib AA, Meir K, Atlan K, Pikarsky E, Parnas O, Dor Y, Zamir G, Ben-Porath I, Krizhanovsky V. Senolytic elimination of Cox2-expressing senescent cells inhibits the growth of premalignant pancreatic lesions. Gut. 2022 Feb;71(2):345-355. doi: 10.1136/gutjnl-2020-321112. Epub 2021 Mar 1. PMID: 33649045; PMCID: PMC8762039.

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