RAS/MAPK Pathway Inhibition as an Example of the Way in Which Cancer Research Informs Aging Research
A sizable number of potential approaches to slowing aging via metabolic manipulation were first tested in the cancer research community. In part, this is because that side of the research community has tested near every compound in the libraries at some point in time, but it is also the case there are deep ties between approaches that might impact cancer and changes that might slow aging. This is particularly the case in the matter of cellular senescence, of great relevance to both cancer and aging, and the first senolytic drugs to clear senescent cells had already seen some success in the cancer field. In at least one case, dasatinib, this success is likely precisely because it is a senolytic, and senescent cells encourage growth of the leukemias that the dasatinib is used to treat.
More often, however, the outcome for aging is not as dramatic as is the case for senolytics. Slowing aging is a usually a marginal affair, achieved by triggering cellular stress response mechanisms, or influencing growth and energy metabolism in some way. The gains in humans will most likely be much smaller than those achieved in mice, judging from the existing points of comparison, such as practice of calorie restriction, or populations with loss of function mutations affecting growth hormone signaling, such as Laron syndrome. Today's open access paper is an example of this sort of age-slowing intervention, well-explored in the cancer research community, and which may gain some interest in the aging research community. Yet we shouldn't expect this to result in any wondrous new therapies to treat aging in humans.
Molecular inhibition of RAS signalling to target ageing and age-related health
Ageing research in model organisms has led to the rapid identification and genetic dissection of key ageing pathways, including the RAS/MAPK signalling pathway. Genetic interventions that modulate signalling through RAS proteins and their downstream effectors have been shown to increase lifespan in these model systems and to improve multiple parameters of health, both during normal ageing and in animal models of age-related disease. RAS/MAPK signalling therefore adds to an emerging theme that manipulating cancer-promoting pathways, either by inhibiting the function of oncogenes or by increasing the activity of tumour suppressors, can affect healthy ageing.
Examples from rodent models that extend lifespan include Myc haploinsufficiency, extra genomic copies of the Ink4/Arf locus, that elevate expression of its encoded tumour suppressor proteins p16 and p14, and increased gene dosage of the tumour suppressor Pten, or mimicking its activation through genetic inhibition of its direct target, PI3K. Interestingly, although some these models had reduced cancer incidence, researchers also observed lifespan extension in cancer-free animals, suggesting that delayed ageing may not simply be a consequence of protection against cancer.
The prominent role of RAS/MAPK signalling in cancer has led to the isolation of several small molecule inhibitors of the pathway, and some are already in clinical use. Recent work with model organisms suggests that these same compounds may provide beneficial effects on age-related health. Thus, repurposing these anti-cancer treatments could provide a useful strategy to develop novel interventions to promote healthy ageing. Moreover, other pro-longevity pharmacological interventions may elicit their effects on ageing and age-related health, at least in part through perturbations in RAS/MAPK signal transduction. It should be noted, though, that compounds like metformin, acarbose, dihydromyricetin, and statins have much broader effects, and, although they have an impact on RAS/MAPK outputs, they do not exclusively target this pathway.
However, cancer therapeutics, including small molecule inhibitors of RAS/MAPK signalling, are notoriously toxic and can elicit severe side effects. Effective strategies to limit these adverse effects will therefore be essential for clinical implementation. Determining the critical time periods during the life course when RAS/MAPK inhibition modulates ageing, and assessing the effect of intermittent dosing, could be one such approach to minimise side effects. Careful titration will also help to provide the geroprotective effects of these drugs without side effects or drug resistance.