Challenges in anti-aging medicine-trends in biomarker discovery and therapeutic interventions for a healthy lifespan

Abstract

We are facing a growing aging population, along with increasing pressure on health systems, caused by the impact of chronic co-morbidities (i.e. cancer, cardiovascular and neurodegenerative diseases) and functional disabilities as people age. Relatively simple preventive lifestyle interventions, such as dietary restriction and physical exercise, are important contributors to active and healthy aging in the general population. However, as shown in model organisms or in 'in vitro' conditions, lifestyle-independent interventions may have additional health benefits and can even be conceived as possible reversers of the aging process. Thus, pharmaceutical laboratories, research institutes, and universities are putting more and more effort into finding new molecular pathways and druggable targets to develop gerotherapeutics. One approach is to target the driving mechanisms of aging, some of which, like cellular senescence and impaired autophagy, we discussed in an update on the biology of aging at AgingFit 2023 in Lille, France. We underline the importance of carefully and extensively testing senotherapeutics, given the pleiotropism and heterogeneity of targeted senescent cells within different organs, at different time frames. Other druggable targets emerging from new putative mechanisms, like those based on transcriptome imbalance, nucleophagy, protein phosphatase depletion, glutamine metabolism, or seno-antigenicity, have been evidenced by recent preclinical studies in classical models of aging but need to be validated in humans. Finally, we highlight several approaches in the discovery of biomarkers of healthy aging, as well as for the prediction of neurodegenerative diseases and the evaluation of rejuvenation strategies.

Keywords: autophagy; biomarkers; centenarians; inflammaging; lifespan; lifestyles; rejuvenation; senescence; senolytics; senomorphics.

FIGURE 1

Senomorphic molecules (and their targets) tested in clinical trials in old adults (>65 years) for: breast cancer, colorectal cancer, Covid‐19, etc. (apigenin, kaempferol); age‐related sarcopenia, heart failure, transplantation, solid tumors, longevity, etc. (rapamycin); rheumatoid arthritis, various types of cancers, Covid‐19, etc. (tocilizumab); cytokine storm (in Covid‐19), lymphoma, gout, CKD, heart failure, T2D, pancreatic cancer, etc. (anakinra); glaucoma, inflammatory bowel disease, psoriasis, rheumatoid arthritis, etc. (infliximab); prostate cancer, HCC, leukemia, etc. (ruxolitinib). www.ClinicalTrials.gov. SASP, senescent‐associated secretory phenotype (comprising pro‐inflammatory cytokines, chemokines, growth factors, and extracellular matrix proteases); SenC, senescent cell.