If there is to be a simple, sensible, consensus position on the treatment of aging as a medical condition, it might run something like this. (a) If our species is going to put significant time and funding into this project, then it is much better to conduct research and development programs that are capable of achieving rejuvenation, rather than those that can achieve only a slowing of aging. (b) Similarly, more rejuvenation is better than less rejuvenation. We should aim to optimize the direction of development as early as possible. (c) At present it is challenging, slow, and expensive to assess the benefits produced by an alleged rejuvenation therapy, particularly in long-lived species such as our own. (d) Thus it is important to develop the capability to assess biological age immediately before and after treatment, via robust, accurate, low-cost approaches. (e) Epigenetic, transcriptomic, and proteomic clocks offer the most likely path to such a viable assessment of biological age. (f) Developing a consensus, validated clock should be a priority alongside development of the first few potential rejuvenation therapies to have performed well to date in mice.
The authors of today's open access paper argue much along these lines. The corresponding author, Vadim Gladyshev, is actually not that optimistic about the likely pace of progress towards meaningful human rejuvenation in our lifetimes. He nonetheless has a sensible attitude towards the bigger picture, one of a network of large-scale research and development programs that will ultimately lead towards many different successful interventions targeting the processes of aging.
Despite the great promise of clocks to assess biological age, and the proliferation of such clocks discovered via machine learning approaches, this technology is not yet capable of producing unbiased measures of the effectiveness of new therapies. The challenge is that researchers as yet have little idea as to what, in detail, causes specific age-related changes in the epigenome, transcriptome, and proteome. Thus any use of a clock to assess a new approach to therapy must first be calibrated against life span studies, in mice at the very least, before we can take any of the resulting data seriously. The research community should prioritize this area of research, along with the first few candidate rejuvenation therapies likely to produce a large enough reversal of biological age to test the clocks.
As the most significant risk factor for human mortality, aging leads to functional decline, increased frailty, and elevated susceptibility to chronic disease. The current strategies for human lifespan extension can be divided into three major categories: (i) those that treat direct causes of mortality, (ii) those that slow down or attenuate the biological aging process, and (iii) those that achieve rejuvenation (i.e., the reversal of aging).
The first category involves treatments for age-related diseases, such as pharmaceuticals for COVID-19 in humans or age-related cancers in mice. Antibiotics, which single-handedly shifted the main cause of death in humans and extended lifespan by several decades, also belong to this category. The second involves lifespan extension in healthy individuals, without evident age reversal. One example in this category is lifespan extension caused by mild stressors such as heat, cold, or irradiation. The third category, rejuvenation, has long been regarded as the panacea for age-related diseases, but it has previously been deemed unrealistic.
While the first two major strategies have been extensively studied, very little is known about the systemic reversal of organismal aging. This is in part due to the lack of longitudinal data and validated quantitative readouts of rejuvenation, and also by the general belief that aging is inevitable and unidirectional. However, several putative rejuvenation therapies have recently been introduced that demonstrated age reversal as measured by aging biomarkers and physiological readouts. Despite these advances, whether systemic rejuvenation can be achieved by these approaches and how they can be translated to human applications remains unclear.
Distinguishing potential rejuvenation therapies from other longevity interventions, such as those that slow down aging, is challenging, and these anti-aging strategies are often referred to interchangeably. We suggest that the prerequisite for a rejuvenation intervention is a robust, sustained, and systemic reduction in biological age, which can be assessed by biomarkers of aging, such as epigenetic clocks. We discuss known and putative rejuvenation interventions and comparatively analyze them to explore underlying mechanisms.