Young Adults With Sickle Cell Disease Have Elevated p16 mRNA, Contributing to Premature Aging

Young adults and adolescents with sickle cell disease (SCD) have increased expression of p16^INK4a (p16) mRNA in peripheral T-cell lymphocytes, leading to significantly higher cellular senescence burden that contributes to premature aging, excess morbidities, and physiological decline, according to study results published in Aging.¹

Premature aging can be a complication of patients with sickle cell disease. | Image Credit: © Dr_Microbe | stock.adobe.com

Patients with SCD today have many treatment options due to advances in therapy, meaningfully increasing life expectancy in recent decades. Still, patients of all ages with SCD deal with disproportionate functional decline, frailty, and heightened rates of premature end-organ damage and malignancies.^1,2

Cellular senescence is a hallmark of biological aging and has been identified in numerous studies as a significant contributor to decline and aging-related complications. The process occurs when cells cease dividing but continue to send damaging signals to surrounding tissues. A reliable biomarker of cellular senescence is p16; increased expression of p16 in peripheral blood T lymphocytes has been associated with well-established pro-aging exposures.^1,3

Given the previous indications of p16’s usefulness as an indicator of age-related conditions, the investigators hypothesized that p16 expression would be elevated in patients with SCD. Thus, they conducted an analysis of adolescents and young adults with SCD and compared them with similarly aged individuals without SCD to determine the presence of p16 and subsequent patient outcomes.¹

The final analysis included 18 adolescents and young adults with SCD, and 27 comparator participants. The results indicated that participants with SCD had significantly higher p16 expression compared with comparator individuals (−10.1 vs 8.7 log₂ p16 units). Further data, based on prior analysis of the regression of p16 expression by chronological age, showed that the mean difference of 1.3 log₂ units (95% CI; 0.79–1.9, P <.001) between the SCD and comparator groups may be as much as 43 years (95% CI; 23–63 years) of increased biological aging.¹

“These initial results suggest that individuals with SCD have a significantly higher cellular senescence burden, which may contribute to premature aging, physiological decline, and excess morbidities,” investigators from the news release wrote. “Our youngest participant, a 15-year-old with SCD, had a higher p16 expression than all the comparators, underscoring the early rise of p16 expression in this population.”³

Notably, the researchers found similar results when stratifying by chronic transfusion therapy (CTT), which is a treatment for severe SCD complications such as stroke. Data indicated that the mean difference in p16 expression between the patients with SCD on CTT and comparators was 1.3 log₂ p16 units (10.0 vs 8.7 log₂ p16 units, P =.002), while the difference between the SCD participants not on CTT and comparators was 1.4 (10.1 vs 8.7 log₂ p16 units, P =.001).¹

Investigators discussed that this faster aging could be a result of chronic inflammation, lack of oxygen, and stress on the body that is associated with SCD. They noted that the major differences were unexpected and that the differences were even larger than those between young adult cancer survivors treated with pro-aging exposures and the same comparator group featured in the trial. Despite these notable results and postulation regarding the etiology, the exact mechanisms behind the heightened p16 expression in SCD remain unknown.^1,3

“While further prospective research is needed to establish the clinical implications and predictive utility for elevated p16 expression in patients with SCD, these initial findings provide molecular evidence of biological aging beginning at a young age in individuals living with SCD,” the study authors concluded.¹

REFERENCES

1. Wilson SR, Mitin N, Miller VLA, et al. Adolescents and young adults with sickle cell disease exhibit accelerated aging with elevated T-cell p16^INK4a expression. Aging. 2024;16(21):13225-13236. doi:10.18632/aging.206152

2. Thein SL, Howard J. How I treat the older adult with sickle cell disease. Blood. 2018;132(17):1750-1760. doi:10.1182/blood-2018-03-818161

3. Impact Journals LLC. Accelerated aging in young sickle cell patients linked to elevated T-cell p16INK4a. EurekAlert! News Release. Released December 11, 2024. Accessed January 31, 2025.