Marked aging-related decline in efficiency of oxidative phosphorylation in human skin fibroblasts.
An extensive analysis has been carried out of mitochondrial biochemical and bioenergetic properties of fibroblasts, mostly skin-derived, from a large group of subjects ranging in age between 20 wk fetal and 103 yr. A striking age-related change observed in a fundamental process underlying mitochondrial biogenesis and function was the very significant decrease in rate of mitochondrial protein synthesis in individuals above 40 yr. The analysis of endogenous respiration rate revealed a significant decrease in the age range from 40 to 90 yr and a tendency to uncoupling in the samples from subjects above 60 yr. A surprising finding was the occurrence of a subgroup of individuals >or=90 yr old whose skin fibroblasts exhibited an exceptionally high respiration rate. This high rate was not due to respiration uncoupling, rather pointing to a compensatory phenomenon, not involving an increase in mtDNA content, in the corresponding skin fibroblast populations, or, possibly, to a selection of a different cell type secondary to more extensive dermal atrophy. The most important aging-related phenotypic effects observed were those that affected the cell oxidative phosphorylation (OX-PHOS) capacity. These were, in particular, the very significant reduction in the ratio of uncoupled to oligomycin-inhibited endogenous respiration observed in intact fibroblasts, which pointed to a decrease with donor's age in the control of respiration by the mitochondrial membrane potential, the very significant decrease in efficiency of OX-PHOS, as determined by novel in situ measurements of P:O ratios, and, consistent with these results, the very significant reduction in the respiratory control ratios. These findings clearly pointed to a dramatic mitochondrial dysfunction, which would lead to a decrease in ATP synthesis rate, with the observed decline in mitochondrial protein synthesis rate being a likely contributing factor. These observations have important implications for understanding the biology of aging, as well as the pathogenesis of aging-related degenerative diseases.
Greco
Marilena
M
Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
Villani
Gaetano
G
Mazzucchelli
Franca
F
Bresolin
Nereo
N
Papa
Sergio
S
Attardi
Giuseppe
G
D000293:Adolescent; D000328:Adult; D000368:Aged; D000375:Aging; D019069:Cell Respiration; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005333:Fetus / Q000166:cytology; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D007223:Infant; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000096:biosynthesis; D008954:Models, Biological; D010085:Oxidative Phosphorylation; D012867:Skin / Q000166:cytology*; D014407:Tumor Cells, Cultured
D024101:Mitochondrial Proteins