Every major cause of death and disability in the developed world shares a greatest risk factor, and it is probably not what most people would think. Smoking, obesity, a sedentary lifestyle and drinking too much alcohol all contribute to disease: however, their contributions are small in comparison to the physiological changes that result from aging. Whether biological aging causes the many functional declines that occur with age, or just permits them, is perhaps open for debate, but there is no question that, for most of us, biological aging determines how and when we and our loved ones will get sick and die.
This connection between aging and disease has become particularly consequential during the COVID-19 pandemic, with the vast majority of severe cases and deaths occurring among the elderly. Given this obvious relationship, it is somewhat surprising how slowly the biomedical research community has come to appreciate the importance of biological aging in many of the disease processes under study. It is our hope that the articles in the eLife special issue on aging, geroscience and longevity will contribute to a greater appreciation and understanding of aging biology among the broader scientific community. A number of the authors of these articles also spoke at a recent eLife symposium on this topic.
Today, unfortunately, too many scientists study individual diseases without recognizing the impact of aging biology. It is still common, for example, to see research studies in cancer, neuroscience, metabolism and other fields where young animal models (such as 4–6 month old mice) are used to study disease processes that almost exclusively occur in old people. ‘Mice are not people’ is a standard refrain when explaining why so many preclinical therapies fail in human trials. Perhaps the mouse isn’t the problem. Failing to account for the physiological changes that occur during aging, both in mice and in people, may be a much bigger reason why so much preclinical research fails to translate to the clinic.
It is still common to see research studies in cancer, neuroscience, metabolism and other fields where young animal models are used to study disease processes that almost exclusively occur in old people.
Thinking about certain conserved molecular mechanisms as 'hallmarks' or 'pillars' of aging (Kennedy et al., 2014; López-Otín et al., 2013) has benefitted researchers within the field, and has also allowed scientists outside the field to begin to recognize how aging biology impacts on their own research. Many of these conserved mechanisms are studied in the papers in this special issue, including telomere attrition, mitochondrial dysfunction, cellular senescence, epigenetic alterations, stem cell exhaustion, genomic instability, and loss of proteostasis.
Another important advance in aging research has been the development of a concept called geroscience: researchers in this area seek to understand mechanistically how the hallmarks of aging cause age-related disease and functional decline (Sierra and Kohanski, 2017). The growth of the geroscience concept also reflects a recognition that aging research is much closer to clinical application than it was twenty years ago. Numerous interventions have been developed that target one or more of the hallmarks of aging in order to delay, or even reverse, age-related functional declines. In rodents, for example, it has been shown that the drug rapamycin can prevent age-related diseases and improve function in multiple aged tissues and organs. Now, in the eLife special issue on aging, An et al. report that rapamycin also works in the oral cavity and can reverse periodontal disease in mice (An et al., 2020). Other articles suggest translational strategies to target specific hallmarks of aging for intervertebral disc degeneration (Cherif et al., 2020) and age-related heart disease (Chiao et al., 2020). At the time of writing there are two review articles and more than 20 research articles in the special issue, and more will be added over time.
The future of aging research is brighter than ever before, and the pace of discovery is only increasing. We look forward to major breakthroughs over the next few years that will revolutionize the way we think about aging biology and have the potential to significantly impact human healthspan and longevity.
Leucine-rich repeat kinase 2 (LRRK2) variants associated with Parkinson’s disease (PD) and Crohn’s disease lead to increased phosphorylation of its Rab substrates. While it has been recently shown that perturbations in cellular homeostasis including lysosomal damage can increase LRRK2 activity and localization to lysosomes, the molecular mechanisms by which LRRK2 activity is regulated have remained poorly defined. We performed a targeted siRNA screen to identify regulators of LRRK2 activity and identified Rab12 as a novel modulator of LRRK2-dependent phosphorylation of one of its substrates, Rab10. Using a combination of imaging and immunopurification methods to isolate lysosomes, we demonstrated that Rab12 is actively recruited to damaged lysosomes and leads to a local and LRRK2-dependent increase in Rab10 phosphorylation. PD-linked variants, including LRRK2 R1441G and VPS35 D620N, lead to increased recruitment of LRRK2 to the lysosome and a local elevation in lysosomal levels of pT73 Rab10. Together, these data suggest a conserved mechanism by which Rab12, in response to damage or expression of PD-associated variants, facilitates the recruitment of LRRK2 and phosphorylation of its Rab substrate(s) at the lysosome.
Activating mutations in the leucine-rich repeat kinase 2 (LRRK2) cause Parkinson’s disease. LRRK2 phosphorylates a subset of Rab GTPases, particularly Rab10 and Rab8A, and we showed previously that these phosphoRabs play an important role in LRRK2 membrane recruitment and activation (Vides et al., 2022). To learn more about LRRK2 pathway regulation, we carried out an unbiased, CRISPR-based genome-wide screen to identify modifiers of cellular phosphoRab10 levels. A flow cytometry assay was developed to detect changes in phosphoRab10 levels in pools of mouse NIH-3T3 cells harboring unique CRISPR guide sequences. Multiple negative and positive regulators were identified; surprisingly, knockout of the Rab12 gene was especially effective in decreasing phosphoRab10 levels in multiple cell types and knockout mouse tissues. Rab-driven increases in phosphoRab10 were specific for Rab12, LRRK2-dependent and PPM1H phosphatase-reversible, and did not require Rab12 phosphorylation; they were seen with wild type and pathogenic G2019S and R1441C LRRK2. As expected for a protein that regulates LRRK2 activity, Rab12 also influenced primary cilia formation. AlphaFold modeling revealed a novel Rab12 binding site in the LRRK2 Armadillo domain, and we show that residues predicted to be essential for Rab12 interaction at this site influence phosphoRab10 and phosphoRab12 levels in a manner distinct from Rab29 activation of LRRK2. Our data show that Rab12 binding to a new site in the LRRK2 Armadillo domain activates LRRK2 kinase for Rab phosphorylation and could serve as a new therapeutic target for a novel class of LRRK2 inhibitors that do not target the kinase domain.