Targeting the "hallmarks of aging" to slow aging and treat age-related disease: fact or fiction?

Aging is a major risk factor for a number of chronic diseases, including neurodegenerative and cerebrovascular disorders. Aging processes have therefore been discussed as potential targets for the development of novel and broadly effective preventatives or therapeutics for age-related diseases, including those affecting the brain. Mechanisms thought to contribute to aging have been summarized under the term the "hallmarks of aging" and include a loss of proteostasis, mitochondrial dysfunction, altered nutrient sensing, telomere attrition, genomic instability, cellular senescence, stem cell exhaustion, epigenetic alterations and altered intercellular communication. We here examine key claims about the "hallmarks of aging". Our analysis reveals important weaknesses that preclude strong and definitive conclusions concerning a possible role of these processes in shaping organismal aging rate. Significant ambiguity arises from the overreliance on lifespan as a proxy marker for aging, the use of models with unclear relevance for organismal aging, and the use of study designs that do not allow to properly estimate intervention effects on aging rate. We also discuss future research directions that should be taken to clarify if and to what extent putative aging regulators do in fact interact with aging. These include multidimensional analytical frameworks as well as designs that facilitate the proper assessment of intervention effects on aging rate.