Could cancer drugs provide ammunition against aging?

Recent advances in our understanding of the molecular and cellular signaling pathways that drive aging have revealed several genetic and environmental manipulations that can increase lifespan across different species. Research on the underlying biology of aging has not only revealed it to be a biologically malleable process but has also paved the way for the development of pharmacological interventions that could increase lifespan and delay the onset and/or progression of age-related disease.

An emerging theme from recent studies is that manipulating the activity of cancer-promoting pathways, by increasing the activity of tumor suppressor proteins or inhibiting the function of oncogenes, can extend lifespan. For example, increasing the gene dosage of the tumor suppressor Pten or genetic inhibition of its direct target, the Class 1 phosphatidylinositol 3-kinase (PI3K), equivalent to PTEN activation, extends lifespan in mice.^1,2 Moreover, an extra genomic copy of the Ink4/Arf locus, resulting in elevated expression of its encoded tumor suppressor proteins, extends lifespan,³ while mice haploinsufficient for the Myc oncogene live longer than their wild-type littermates.⁴ Interestingly, while cancer incidence was reduced in several of these models, lifespan extension was also observed in cancer-free individuals, suggesting that cancer protection and delayed aging are separable effects of the genetic manipulations imposed.

We have now added inhibition of oncogenic Ras-Erk-ETS signaling to this anti-aging mix.⁵ Hyperactivation of the Ras oncogene is believed to be responsible for around 30% of all human tumors. The Ras proteins function as small GTPases, cycling between inactive GDP-bound and active GTP-bound states to transmit signals from receptor tyrosine kinases (RTKs). Activation of Ras therefore leads to the induction of several RTK signaling pathways including the extracellular signal-regulated kinase (Erk)/mitogen activated protein kinase (Mapk) signaling cascade.

Using the fruit fly, Drosophila melanogaster, we selectively mutated the insulin receptor substrate, chico, to disrupt either of the 2 key outputs of insulin/IGF-like signaling (IIS) in flies, Ras-Erk-ETS or PI3K-AKT-Foxo signaling.⁵ We found that selective inhibition of signaling through either of these pathways increased longevity. Moreover, direct genetic inhibition of Ras or Erk extended lifespan through activation of the E-twenty six (ETS) transcription factor, Anterior Open (AOP). We showed that lifespan extension by Erk or PI3K inhibition was not additive, suggesting that the 2 pathways converge on a common set of genes to regulate lifespan. Indeed, the 2 down-stream effectors of the 2 branches, the transcription factors Foxo and AOP, can be found occupying the same genomic sites. Importantly, we demonstrated that exposure of adult flies to trametinib, a small molecule inhibitor of Erk activation, currently in clinical use as a cancer therapy, extended their lifespan. While the exact targets and/or processes affected remain unknown, it would seem that, as with other cancer prevention pathways, the anti-aging effects of Ras inhibition are separable from its anti-cancer activity because trametinib exposure at doses conducive to lifespan extension did not alter the cancer-like pathology of extensive proliferation of the adult intestinal stem cells.

So if cancer prevention is not responsible for lifespan extension in these animals then what is? One potential mechanism by which these animals live longer could be through the promotion of beneficial metabolic changes. For example, Myc^+/− mice have a higher metabolic rate and show a more youthful metabolic transcriptome at older ages.⁴ Mice with overexpression of PTEN have increased energy expenditure and are protected from obesity and metabolic syndrome¹ while long-term inactivation of PI3K results in age-related reductions in insulin insensitivity, glucose intolerance and fat accumulation.² It remains to be determined whether inhibiting Ras-Erk-ETS signaling can extend mammalian lifespan but, intriguingly, inhibition of Erk activation in mice using trametinib can improve several deleterious metabolic outcomes associated with obesity as a result of high-fat feeding or genetic intervention.⁶ Thus, targeting the activity of these cancer prevention pathways may confer longevity effects by offering protection from metabolic pathologies during aging, independently of effects on cancer (Fig. 1). It is worth noting that the beneficial metabolic effects of trametinib in mice were observed at much lower doses than those used in xenograft tumor models⁶ suggesting that the therapeutic window of these compounds for anti-aging effects may be much safer than for cancer treatment and with fewer side-effects.

Figure 1.

Inhibiting the activity of cancer-promoting pathways extends lifespan. Upregulating the activity of tumor suppressor proteins or inhibiting oncogene function not only protects against cancer but also promotes several beneficial metabolic effects including the prevention of obesity. These changes in metabolism may contribute to cancer prevention but their effects on longevity appear to be independent from their anti-cancer functions. Pharmacological manipulation of these pathways could therefore confer longevity effects independently of cancer prevention by protecting against deleterious metabolic changes during aging. Importantly, initial studies suggest that these metabolic changes are elicited at much lower doses than for cancer prevention producing fewer side effects.

The connections between cancer prevention and longevity are obviously complex. For example, cellular senescence, an important mechanism for tumor suppression, is often described as a contributing factor in age-related pathologies.⁷ Nevertheless, the anti-aging effects of reducing cancer-promoting pathways opens up the intriguing possibility that repurposing the available goldmine of cancer drug therapies could offer new treatments for other age-related diseases and possibly even key aspects of aging itself.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.