From molecular promise to preclinical results: HDAC inhibitors in the race for healthy aging drugs

Abstract

Reversing or slowing the aging process brings great promise to treat or prevent age-related disease, and targeting the hallmarks of aging is a strategy to achieve this. Epigenetics affects several if not all of the hallmarks of aging and has therefore emerged as a central target for intervention. One component of epigenetic regulation involves histone deacetylases (HDAC), which include the "classical" histone deacetylases (of class I, II, and IV) and sirtuin deacetylases (of class III). While targeting sirtuins for healthy aging has been extensively reviewed elsewhere, this review focuses on pharmacologically inhibiting the classical HDACs to promote health and longevity. We describe the theories of how classical HDAC inhibitors may operate to increase lifespan, supported by studies in model organisms. Furthermore, we explore potential mechanisms of how HDAC inhibitors may have such a strong grasp on health and longevity, summarizing their links to other hallmarks of aging. Finally, we show the wide range of age-related preclinical disease models, ranging from neurodegeneration to heart disease, diabetes to sarcopenia, which show improvement upon HDAC inhibition.

Keywords: HDAC inhibitors; epigenetics; geroprotector; hallmarks of aging; preclinical models.

Figure 1. Potential models whereby HDAC inhibition (HDACi) extends lifespan

(A) HDACi may directly reverse age‐related deacetylation of chromatin, reverting the epigenome back to a more youthful state. (B) HDACi may result in acetylation of histones near pro‐longevity genes, increasing their transcription. (C) HDACi may act through a hormesis effect, causing low dose damage that activates stress resistance, resulting in a net benefit for the organism. (D) HDACi may target non‐histone proteins, activating pro‐longevity proteins, and/or de‐activating anti‐longevity proteins.

Figure 2. Influence of HDAC inhibition on the hallmarks of aging

HDAC inhibitors are listed as described in the text, along with evidence for the benefits they impart at the molecular level on the hallmarks of aging; epigenetic alterations, telomere attrition, genomic instability, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication, and up‐ or downregulated processes are generally in line with beneficial changes for the health of the organism, while altered changes are indicative of potential synergies and interactions.

Figure 3. Benefits of HDAC inhibitors in preclinical models

HDAC inhibition benefits a large variety of preclinical models, including those related to neurodegeneration, cardio‐metabolic deficiencies, liver dysfunctions, sarcopenia, inflammation‐related disease, and diseases of premature aging. Specifics of improvements in each condition are described in the text.