The hallmarks of aging are exactly that, hallmarks. They are not intended to be a list of causative mechanisms, though it appears that some people take it that way, particularly if it is supportive to their research and development program choices. Some of the hallmarks of aging overlap with the Strategies for Engineered Negligible Senescence (SENS) list of proposed causative mechanisms of aging, and the hallmarks paper itself clearly owes much to earlier SENS publications, as well as parallel proposals such as the Seven Pillars of Aging. It is important to target causes rather than consequences when it comes to aspects of aging, as only the treatment of causes is likely to be effective. The field is overdue a more broad, high-profile critique and consideration of the hallmarks of aging from the perspective of identifying causative mechanisms for intervention, rather than simply describing aging.
In a recent review article researchers conducted an exhaustive literature review and described an updated 12 hallmarks of aging. The updated model of aging comprehensively captures the key characteristics of the aging phenotype and incorporates new pathways that play a crucial role in age-related processes. Although the updated hallmarks of aging provide a useful framework for describing the phenotype of aging, aging itself is a result of mechanistically complex and interrelated processes that happen during the lifespan of the organism. Here, I propose to shift the focus from a systematic description and categorization of the hallmarks of aging to a model that separates the early, molecular origins of changes from cellular and tissue responses and represents the sequential and causative character of changes in aging. The proposed model aims to prompt discussion among the aging research community, guide future efforts in the field, and provide new ideas for investigation.
When the original 9 hallmarks of aging were first introduced in 2013, little was known about the mechanisms of aging. Since then, many research groups have described various mechanisms underlying this process, introducing the concept of the sequential character of changes in time and the molecular basis of the process. Therefore, I believe that the hallmarks of aging will benefit from the inclusion of information of temporal and sequential character of the process of aging. The aging process is commonly divided into early and late events, with a clear distinction between aging phenotypes and the underlying molecular events. Aging encompasses molecular, physiological, and phenotypic changes with different clinical relevance and different short-term or long-term outcomes if targeted using pharmacological interventions. Therefore, I propose a "three-wheeled gears" model to describe the early (upstream), intermediate, and late (downstream) events.
Any type of stress/disturbance can induce epigenetic changes, transcriptional noise, nuclear DNA damage and mitochondrial DNA damage, loss of cell membrane integrity, and oxidative stress, among other molecular disturbances. Intermediate events of aging encompass cellular responses to stress-induced molecular alterations and include activation of inflammation, proteostasis, autophagy, senescence, establishing energy homeostasis, and rewiring of cellular metabolism. If not resolved, molecular and cellular alterations due to repeated stress throughout the life of the individual trigger late events of aging, which manifest as aging phenotypes. Late events of aging result in progressive deterioration of organ function and include stem cell exhaustion, organ dysfunction, loss of tissue integrity, immune system dysfunction, for example, chronic low levels of inflammation, and alterations in tissue-tissue interactions and cell-cell communication. Molecular, cellular, and phenotypic processes of aging are interconnected, and progression in one process induces the progression of all other processes.
At present, investigational therapeutic approaches targeting aging phenotypes are geared mostly toward reverting aging symptoms rather than targeting the underlying molecular and cellular mechanisms. However, recognizing the aging phenotype is crucial for deciphering the mechanisms underlying aging and age-related diseases. We cannot fully delineate complex biological processes such as aging without addressing the molecular and cellular mechanisms that contribute to the different characteristics of aging and without dissecting the temporal and causal sequence of events.