The rationale for testing drug combinations in aging intervention studies
Aging is a complex process driven by seven intertwined pillars that functionally decline with increasing chronologic age. These pillars of aging include stem cell function, mitochondrial function, proteostasis, autophagy, nutrient sensing, metabolism, epigenetic control, and adaptation to stress, macromolecular damage and inflammation. All of the pillars appear to be interconnected such that a change in one, impinges upon others. With so many pillars of aging, it makes drug development to target aging processes equally complex. This leads to the notion that multiple pathways or biological processes need to be targeted to effectively prevent, delay or attenuate aging. The concept of drug combinations as a powerful anti-aging platform is intriguing but has yet to be tested systematically. Insulin function, mTOR (mammalian target of rapamycin) signaling and epigenetic regulation are well-established molecular pathways involved in the pathobiology of aging. Existing drugs that target these pathways include acarbose, rapamycin, and phenylbutyrate, respectively. Acarbose and rapamycin, used as single agents, extend the lifespan of mice. Thus, a cocktail of these drugs with different mechanisms of action would be expected to complement one another and robustly enhance a delay of aging and age-related disease not achievable with mono-therapeutic approaches. Studies to test this concept will be helpful in the development of clinical trials to enhance healthy aging.