Mitochondria power-supply failure may cause age-related cognitive impairment

Good news! Towards beating the ravages of age!

"... “Fifty percent of people experience loss of working memory with old age, meaning their ability to hold and manipulate information in the short-term decreases,” ... “We set out to understand why some individuals maintain healthy working memory as they age, while others do not. In the process, we discovered a novel mechanism for the synaptic basis of cognitive impairment.” ...
“Investigating these microscopic dysfunctions is uncharted territory that could revolutionize our understanding of aging and its impact on cognition.” ..."

From the abstract:

"Morphology and function of the dorsolateral prefrontal cortex (dlPFC), and corresponding working memory performance, are affected early in the aging process, but nearly half of aged individuals are spared of working memory deficits. Translationally relevant model systems are critical for determining the neurobiological drivers of this variability. The common marmoset (Callithrix jacchus) is advantageous as a model for these investigations because, as a non-human primate, marmosets have a clearly defined dlPFC that enables measurement of prefrontal-dependent cognitive functions, and their short (∼10 year) lifespan facilitates longitudinal studies of aging. Previously, we characterized working memory capacity in a cohort of marmosets that collectively covered the lifespan, and found age-related working memory impairment. We also found a remarkable degree of heterogeneity in performance, similar to that found in humans. Here, we tested the hypothesis that changes to synaptic ultrastructure that affect synaptic efficacy stratify marmosets that age with cognitive impairment from those that age without cognitive impairment. We utilized electron microscopy to visualize synapses in the marmoset dlPFC and measured the sizes of boutons, presynaptic mitochondria, and synapses. We found that coordinated scaling of the sizes of synapses and mitochondria with their associated boutons is essential for intact working memory performance in aged marmosets. Further, lack of synaptic scaling, due to a remarkable failure of synaptic mitochondria to scale with presynaptic boutons, selectively underlies age-related working memory impairment. We posit that this decoupling results in mismatched energy supply and demand, leading to impaired synaptic transmission. We also found that aged marmosets have fewer synapses in dlPFC than young, though the severity of synapse loss did not predict whether aging occurred with or without cognitive impairment. This work identifies a novel mechanism of synapse dysfunction that stratifies marmosets that age with cognitive impairment from those that age without cognitive impairment. ..."

Mitochondria power-supply failure may cause age-related cognitive impairment - Salk Institute for Biological Studies Salk scientists find mitochondria at dysfunctional synapses fail to meet energetic demand, supplying either too much or too little power and potentially causing age-related cognitive impairment

Violation of the ultrastructural size principle in the dorsolateral prefrontal cortex underlies working memory impairment in the aged common marmoset (Callithrix jacchus) (open access)

Normally, the different parts of the synaptic complex grow and shrink together. The researchers found evidence that this process can go awry in aging, which may contribute to cognitive impairment.