Regenerative processes are critical to maintain tissue homeostasis in high-turnover tissues. At the same time, proliferation of stem and progenitor cells has to be carefully controlled to prevent hyper-proliferative diseases. Mechanisms that ensure this balance, thus promoting proliferative homeostasis, are expected to be critical for longevity in metazoans. The intestinal epithelium of Drosophila provides an accessible model in which to test this prediction. In aging flies, the intestinal epithelium degenerates due to over-proliferation of intestinal stem cells (ISCs) and mis-differentiation of ISC daughter cells, resulting in intestinal dysplasia. Here we show that conditions that impair tissue renewal lead to lifespan shortening, whereas genetic manipulations that improve proliferative homeostasis extend lifespan. These include reduced Insulin/IGF or Jun-N-terminal Kinase (JNK) signaling activities, as well as over-expression of stress-protective genes in somatic stem cell lineages. Interestingly, proliferative activity in aging intestinal epithelia correlates with longevity over a range of genotypes, with maximal lifespan when intestinal proliferation is reduced but not completely inhibited. Our results highlight the importance of the balance between regenerative processes and strategies to prevent hyperproliferative disorders and demonstrate that promoting proliferative homeostasis in aging metazoans is a viable strategy to extend lifespan.

Background/Objectives:  The incidence of Prostate cancer is increasing with age and active treatment of high-risk prostate cancer improves survival. However, it is uncertain how the age as contrasted with life expectancy impact treatment decision-making for men with clinically significant prostate cancer. The aim of this study was to determine whether age or life expectancy affected the treatment receipt. Participants: 541 men with high-risk localized prostate cancer (Gleason ≥ 8 or PSA > 20) diagnosed between 2007 and 2013 were recruited to the study. Measurements: Outcome variables included treatment underuse and type of definitive therapies such as radical prostatectomy, radiotherapy, androgen deprivation therapy and cryotherapy. Life expectancy was assessed according to Schonberg Prognostic Index. Results: Among the 541 high-risk prostate cancer patients, older men (≥65 years) received definitive therapy at similar rates as younger men (97% vs 98%; p=0.2), while younger men were more likely to accept surgery compared with older men (95% vs. 72%, p<0.001). Age affected treatment choice depending on the patient's life expectancy. Among men with higher life expectancy, age did not affect surgery receipt (OR=0.62; 95%CI: 0.18-2.20). But among men with lower life expectancy, older age (OR=0.15; 95%CI: 0.06-0.38), black race (OR=0.27; 95%CI: 0.10-0.77), comorbidity (OR=0.31; 95%CI: 0.13-0.76) and non-commercial insurance (OR=0.12, 95%CI: 0.05-0.28) were associated with lower rate of surgical receipt. Conclusion: Although most high-risk prostate cancer patients undergo definitive therapy, both age and life expectancy affected the type of treatment. Clinical decisions appear to be based on patients’ medical condition and long-term outlook, rather than simply age. Non-clinical factors such as race and insurance play a role in treatment decision-making.

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