This open access paper reports on the proceedings at the 2nd Scripps Symposium on the Biology of Aging held earlier this year. Like much of the field now, the focus in unabashedly on intervening in the aging process, which is good to see. Also like much of the field there is still considerable reluctance to talk in public about the potential for rejuvenation and radical life extension, however, rather than aiming at more modest gains. Still, the core message that we should treat aging as a medical condition has now spread far beyond the small groups that started this advocacy. One of the seven SENS rejuvenation research programs needed to reverse aging, senescent cell clearance, has been adopted enthusiastically by the scientific mainstream. These are important and necessary advances on the way towards a future of longer, healthier lives for all.
The goal of the symposium was to bring together leaders in the fields of aging and drug development to discuss strategies for identifying and developing therapeutic approaches to extend human healthspan. This symposium made it highly evident that the biology of aging field is moving quickly toward translational research. At the symposium, there were numerous reports of successful drug screens and drug testing in a variety of model systems. There was also an overall sense of excitement, given that multiple therapeutic modalities, including young plasma, recombinant proteins, and small molecules, extend healthspan and lifespan in model organisms and that clinical trials to test the efficacy of these treatment modalities on healthspan and resilience have been initiated.
The concept of geroscience, defined as the understanding of the relationship between aging and age-related diseases and preventing/delaying disease by targeting fundamental mechanisms of aging, was an underlying theme of the symposium. As reiterated by the keynote speakers, aging is the main risk factor for most chronic diseases. Thus, developing approaches to therapeutically target aging should be a funding priority for the majority of institutes at the National Institutes of Health, as well as other funding agencies, philanthropists, and foundations. The socioeconomic need to extend human healthspan also was made clear. As a consequence of the advances in prevention and treatment of infectious diseases, there will be an unprecedented increase in the number of persons over 65 over the next decades. By 2035, the cost of treating Americans 65 years and older is expected to be over $2 trillion annually. Thus, finding ways to prevent all age-related diseases is one of the most imperative biomedical pursuits.
A common theme arising from the symposium was the need for appropriate model organisms to study aging and age-related disease including models carrying reporters of senescence, mitochondrial function, autophagy and reactive oxygen species (ROS). The use of these reporters or testing of therapeutics needs to be performed in aged model organisms, a problem that has also plagued the cancer field because of the cost and time involved, at least in rodent models. Here, the National Institute on Aging (NIA) Interventions Testing Program in mice (ITP) and in Caenorhabditis elegans (C. elegans) (CITP) have made significant contributions to the identification of drugs/compounds able to extend lifespan. Despite the ITP, CITP, and new models of aging, there still is a need for an expansion of efforts to measure the effects of drugs/compounds on healthspan or resilience, which has greater translational relevance. Thus, many investigators are beginning to incorporate functional analysis of aged mice undergoing therapeutic interventions.
An emerging paradigm in the field of aging is that the burden of senescent cells increases with age in multiple tissues and reducing this senescent cell burden improves healthspan. The reduction of senescent cells in mice reduced atherosclerosis, improved metabolism, prevented tumor metastasis and reduced osteoarthritis in an injury model. Thus, the hunt is on for senolytics or drugs that specifically kill senescent cells. Whether optimized senolytics will have similar positive effects on human healthspan is still unclear, but clinical trials are being planned to determine their effectiveness. It is important to note that it is likely that no one senolytic will be effective in eliminating all types of senescent cells. Individual senolytic compounds are apt to have tissue-specific and even cell type-specific effects. Furthermore, there is increasing evidence that different drivers of senescence can lead to differences in how senescence manifests, which in turn could have a variable impact on the senescent cell's environment.
Adult stem cell function is known to decline with aging. However, it has taken longer to demonstrate that the loss of stem cell function contributes to aging and is not simply a consequence of it. Treatment of a mouse model of accelerated aging with two types of young stem cells extends healthspan and lifespan. Although the exact mechanism for how these stem cell populations affect aging is unknown, preliminary data suggest that their effect is mediated by factors secreted by young, but not old stem cells. These factors appear to reduce cellular senescence and improve the function of endogenous, aged stem cells. Whether these stem cell-derived soluble factors are the same as those found in young plasma is currently unknown. This will undoubtedly remain an area of intense research spanning from continued investigations into fundamental mechanisms of aging to clinical trials.
Clear evidence that the field of aging is moving forward quickly is the number of ongoing or soon-to-be-initiated clinical trials. Importantly, the use of specific short-term clinical endpoints to determine if resilience or function of a specific tissue could be improved is employed to reduce study size, duration, and cost. For example, short-term treatment of a cohort of elderly people with a rapamycin analogue (rapalog) was tested for its ability to improve immune function. The inclusion of additional endpoints provides further information about not only the effect of the intervention on immune function, but also on other aspects of aging that might be modulated and measured in future clinical trials. Similarly, short-term clinical trials with the mitochondrial-targeted SS-31 peptide are in progress for heart disease based on very promising preclinical data. These short-term treatment trials with well-defined, disease-specific endpoints are in contrast to the highly anticipated Treating Aging with Metformin (TAME) trial. The TAME trial is designed to enable evaluating whether metformin extends the healthspan of humans albeit in a rapid 3-5 year format. It is hoped that the TAME trial will serve as a template for pharmaceutical companies to do future testing of drugs aimed at targeting fundamental mechanisms of aging.
It also is clear that support from the private sector will be essential for moving clinical trials forward as there is a huge need for funding from sources other than the NIH to expedite aging research. The successful completion of the first clinical trial demonstrating that human healthspan can be extended is anticipated to instigate tremendous interest in the field by biotech investors and potentially philanthropists. Thus, this first proof-of-principle clinical trial and funding support for it is considered a significant hurdle that must be crossed to accelerate funding and progress in the field.