The smell of aging: an epigenetic blockade in brain cells erodes your sense of smell
Your sense of smell fades as you get older -- something anyone with an elderly grandparent will recognise, yet something science has struggled to explain. New research in fruit flies reveals a surprising mechanism: an epigenetic enzyme that grows more active with age, shutting down the mitochondrial emergency repair system.
Age-related smell loss is no trivial matter. It is an early symptom of neurodegenerative conditions such as Parkinson's and Alzheimer's, and exactly how it develops has long remained unclear. New findings from research on Drosophila -- the fruit fly that has served as a model organism for aging biology for decades -- point to a specific epigenetic pathway.
The enzyme at the centre of the story is called dSetdb1, a so-called histone methyltransferase that attaches a trimethyl group to the histone protein H3 at a specific position (K9). H3K9 trimethylation is a chemical modification that silences genes -- think of it as a flag telling the cell that a stretch of DNA should not be read. As flies get older, the researchers found, dSetdb1 becomes increasingly active in olfactory sensory neurons.
A broken emergency service
The real problem lies in what that heightened methylation switches off. The genes being silenced turn out to be part of the mitochondrial unfolded protein response (UPR-mt), a built-in repair mechanism that kicks in when proteins inside mitochondria become misfolded. Mitochondria are the powerhouses of the cell, and they work hard in actively firing neurons. Damage to mitochondrial proteins is an everyday occurrence; the UPR-mt clears that damage away.
When dSetdb1 cuts off the UPR-mt genes, damaged mitochondria accumulate. In post-mitotic cells -- cells that no longer divide, such as neurons -- that is particularly devastating, because no new cells arrive to replace the damaged ones. The fly's olfactory sensory neurons gradually degenerate, and the sense of smell declines. When the researchers genetically disabled dSetdb1 in older flies, the UPR-mt stayed intact longer and the degeneration of olfactory sensory neurons slowed down.
From fly to human: cautious optimism
The evolutionary conservation of this type of mechanism makes the finding relevant well beyond the fruit fly. H3K9 trimethylation and the mitochondrial stress response are present in all higher organisms, including humans. Whether exactly the same epigenetic lock lands on exactly the same target in human neurons has not yet been proven.
Even so, the study adds to a growing understanding: neuronal aging is not simply the result of wear and tear, but of active biological processes that systematically dismantle the cell's own defences. That means it could, in principle, be influenced -- though the leap from a genetically manipulated fruit fly to a safe treatment in humans is one that is rarely made quickly.