Cellular Senescence Biomarker p16INK4a+ Cell Burden in Thigh Adipose is Associated With Poor Physical Function in Older Women

Abstract

Background: Ample evidence implicates cellular senescence as a contributor to frailty and functional decline in rodents, but considerable effort remains to translate these findings to human aging.

Methods: We quantified senescence biomarker p16INK4a-expressing cells in thigh adipose tissue obtained from older women previously enrolled in a 5-month resistance training intervention, with or without caloric restriction (RT ± CR, n = 11 baseline, 8 pre-post-intervention pairs). Women in this subsample were older (72.9 ± 3.4 y) and overweight/obese (body mass index: 30.6 ± 2.4 kg/m2). p16INK4a+ cells were identified from 12 to 20 random visual fields/sample at 20× magnification (immunohistochemical, nuclear staining) and were present in all adipose samples.

Results: Cross-sectional associations were observed between p16INK4a+ cell burden and physical function, including grip strength (r = -0.74), 400-m walk time (r = 0.74), 4-m gait speed (r = -0.73), and self-perceived mobility (r = -0.78) (p ≤ .05). These relationships remained significant after independent adjustments for age and adiposity (p ≤ .05). p16INK4a+ cell abundance was lower following the intervention (pre: 5.47 ± 3.4%, post: 2.17 ± 1.1% count p16INK4a+ cells, p ≤ .05).

Conclusions: These results provide proof-of-concept that p16INK4a+ cells in thigh adipose are associated with physical function, and may be sensitive to change with RT ± CR in overweight/obese older women.

Figure 1.

Representative images. p16^INK4a+ nuclear cell staining (IHC) of representative adipose tissue sample obtained from single subject. All thigh adipose samples were obtained during biopsy of the vastus lateralis, and were harvested deep to the fascia and likely of intermuscular or perimuscular origin. Upper panels (A, B) 20 × magnification single visual fields with p16^INK4a+ cells (red arrows); bottom panels p16^INK4a+ cell (red flags) distribution across sample section (2×mag, C), and three sections from one sample (1.2× mag, D).

Figure 2.

p16^INK4a+ cell burden before and after 5-mo RT ± CR intervention in older overweight/obese women. p16^INK4a+ cell burden, measured as percent of visual fields with p16 ^INK4a+ cells (A), average p16^INK4a+ cells per field (B), and percent cell count p16^INK4a+ (C), from thigh adipose tissue samples collected before and after a 5-month RT (3 d/wk on weight-stack resistance machines), with a CR intervention designed to elicit moderate weight-loss (–600 kcal/d) or without CR. Black circles: RT only; gray: RT + CR.