HDAC inhibitors are a comparatively poorly understood category of drugs that act to modestly slow aging in short-lived laboratory species. As such, they most likely function through some form of upregulation of cellular stress responses, thus activating cellular maintenance processes that lead to improved cell and tissue function. That said, the chain of cause and effect leading from the known mechanism of action to that stress response upregulation is not clearly mapped. As for all approaches that slow aging via stress response mechanisms, we should remember that the effects on life span in short-lived species are much larger, relatively speaking, than those in long-lived species such as our own, even when the short term effects on the operation of metabolism are quite similar.

Calorie restriction is the canonical example of an intervention that upregulates maintenance processes, such as autophagy, that are activated under conditions of cellular stress. Calorie restriction can extend life span by up to 40% in mice, but certainly doesn't add more than a few years to human life expectancy, even while producing significant benefits to health. Further, therapies that upregulate the same mechanisms as calorie restriction are typically only recreating a fraction of the effects on metabolism, and thus should not be expect to produce the same degree of benefits. This is all worth bearing in mind.

It has become increasingly clear that epigenetics, including DNA methylation, histone modifications, and chromatin state, play a crucial role in the aging process. For example, by assessing changes in DNA methylation patterns, a person's age can be predicted within 5 years of accuracy. Histone modifications, including methylation and acetylation states, have been intimately linked to lifespan regulation. Together, these modifications dictate chromatin state, affecting both gene transcription and genome stability. Epigenetic changes occurring with age provide a tantalizing therapeutic target. In contrast to DNA mutations, epigenetic alterations represent reversible changes, offering the potential for a true "rejuvenating" therapeutic intervention. Of the various epigenetic alterations occurring with age, the influence of histone acetylation, a process balanced by the activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs), on lifespan regulation has been the most characterized, mainly due to the advent of HDAC inhibitors from the cancer biology field. The exact means by which HDAC inhibitors extend lifespan has not been fully resolved; however, a number of possible mechanisms can be envisioned. One possible scenario is that HDAC inhibitors reverse the natural age-related changes occurring in the histone acetylation landscape. This is the most simple explanation for their benefits, supported by the observation that many acetylation marks on histones generally decrease with age and in certain age-related diseases. A second possible mechanism of HDAC inhibitors is that they may affect histones and nucleosomes to directly activate transcription of pro-longevity genes. This is supported by observations that an endogenous HDAC inhibitor, β-hydroxybutyrate (BHB), can increase acetylation in the promoter of the pro-longevity transcription factor FOXO3a resulting in its increased expression, and indeed, BHB's lifespan extending effects depend on HDAC genes. A third possible mechanism through which HDAC inhibitors may increase lifespan is through hormesis. In this scenario, while high doses of HDAC inhibitors may be toxic, low doses would elicit activation of protective genes to regain homeostasis, ultimately improving function. This is supported by observations that flies treated with HDAC inhibitors show upregulation of heat shock protein chaperones, a class of genes that are usually upregulated under stress. A fourth possibility is that HDAC inhibitors may regulate lifespan by modifying the acetylation state of non-histone proteins, activating signaling cascades that promote longevity independent of histone modifications. Despite the promising outlook of HDAC inhibitors for healthy aging, much work remains to be done to better understand their safety and how to minimize adverse side effects. Owing to their origins in the cancer biology field, many cell-type and dose-dependent negative effects of HDAC inhibitors on cell viability have been documented. Careful optimization of dose and drug pharmacokinetics should be made prior to pursuing any strategy in which HDAC inhibitors would be used as a prophylactic drug for healthy aging. More specifically, less-toxic versions of current drugs may be required. Understanding of the mechanism by which HDAC inhibitors extend lifespan is noticeably limited, and many mechanistic options remain. Deeper study of the specific modes of action of these compounds is necessary prior to their implementation as geroprotective compounds.

Link: https://doi.org/10.15252/emmm.201809854