Onset Of Age-related Disorders Research Articles

IRE-1 endoribonuclease activity declines early in C. elegans adulthood and is not rescued by reduced reproduction.

The proteome of a cell helps to define its functional specialization. Most proteins must be translated and properly folded to ensure their biological function, but with aging, animals lose their ability to maintain a correctly folded proteome. This leads to the accumulation of protein aggregates, decreased stress resistance, and the onset of age-related disorders. The unfolded protein response of the endoplasmic reticulum (UPRER) is a central protein quality control mechanism, the function of which is known to decline with age. Here, we show that age-related UPRER decline in Caenorhabditis elegans occurs at the onset of the reproductive period and is caused by a failure in IRE-1 endoribonuclease activities, affecting both the splicing of xbp-1 mRNA and regulated Ire1 dependent decay (RIDD) activity. Animals with a defect in germline development, previously shown to rescue the transcriptional activity of other stress responses during aging, do not show restored UPRER activation with age. This underlines the mechanistic difference between age-associated loss of UPRER activation and that of other stress responses in this system, and uncouples reproductive status from the activity of somatic maintenance pathways. These observations may aid in the development of strategies that aim to overcome the proteostasis decline observed with aging.

Cellular senescence and age-related diseases

Cellular senescence is a state of durable cell cycle arrest after a defined number of cell divisions. The number of population doublings of normal cells in culture depends on the species but not on the types of cells used to establish the culture, showing a positive correlation with the life span of the animals. Therefore, the results suggest a physiological link between a limited proliferative capacity in cell culture and the processes observed in organismal aging. The pivotal role of senescence in organismal aging and the onset of age-related disorders, such as atherosclerosis, type II diabetes, and Alzheimer's disease, is supported by the observation that the clearance of p16-positive senescent cells delays various age-associated disorders and extends healthy lifespan. In this review, I provide an overview of recent advances in understanding the mechanisms underlying the induction of senescence and maintenance of the specific phenotypes, such as senescence associated secretory phenotypes (SASP).