A Rare Epigenetic Accelerated Aging Condition
Accelerated aging conditions are not really accelerated aging conditions; each is a dysfunction in which one specific mechanism runs amok, generating damage and dysfunction that superficially resembles the damage and dysfunction of aging. Most of the known accelerated aging conditions are strongly connected to malfunctions in DNA repair, and dysfunction arises at least in part due to an accumulation of mutational damage in critical cell populations. Here, researchers describe an accelerated aging condition in which the underlying dysfunction is an increase in DNA methylation, distorting the epigenetic regulation of nuclear DNA structure and gene expression, again in ways that are superficially similar to the epigenetic changes of aging. Just as DNA repair disorders provide some insight into normal aging, with caveats, so too we might expect an epigenetic disorder to shed some light. The fine details still matter, however. Dysfunction is not equivalent to accelerated aging, even if it has the appearance of accelerated aging.
Declining tissue function and regenerative capacity underlie many chronic diseases. Experimentally establishing the mechanistic basis for such tissue aging presents substantial challenges, given decades-long timescales and multifactorial origins. Epigenetic alterations have been proposed to have a key etiological role, but whether they are correlative or causal remains a key unanswered question, as does their contribution to specific age-related pathologies.
Here we describe an epigenetically driven accelerated aging syndrome. We demonstrate that DNMT3A gain-of-function mutations in Heyn-Sproul-Jackson syndrome recapitulate age-related gains in DNA methylation (DNAme), cause multilineage stem cell dysfunction, and phenocopy aspects of aging in humans and mice. We also show that region-specific DNA hypermethylation at lineage-specific genes can explain reduced stem cell output and lineage skewing. Hence, starting from a Mendelian disorder, we implicate DNAme-mediated stem cell dysfunction in the etiology of medically important age-related hematological, bone and metabolic pathologies, which might be targetable by future therapies.