Current Limitations of the Integrated Aging Theory Framework and Its TRCS Model
To date, comprehensive validation of the TRCS remains insufficient. Further investigations are required to profile changes in rDNA copy number during cellular senescence across diverse species ranging from plants and nematodes to humans, as well as to characterize the reconstruction of telomeres and rDNA following meiosis in germ cells of these organisms.
Large-scale longitudinal measurements and single-cell resolution data on rDNA shortening in humans are still lacking. The interplay between telomere shortening and rDNA compensation has not been fully elucidated, and the mechanisms underlying telomere and rDNA replenishment in germ cells warrant further exploration.
In addition, systematic rescue experiments are needed to fully verify how elongation of telomere and rDNA arrays affects senescence biomarkers and lifespan at both cellular and organismal levels.
We hope that the Integrated Aging Theory Framework and its TRCS model will stimulate independent experimental testing by scientists worldwide and contribute to further advances in aging biology, cellular senescence, and healthy longevity.