The Yankner lab discovered that the REST transcriptional repressor plays a central role in the aging human brain. REST is activated in a variety of aging brain cell types during aging, regulating a stress resistance gene network that protects that brain from a variety of oxidative, proteostatic and metabolic stressors. Moreover, REST activates a neurodegeneration checkpoint that suppresses key pathogenic proteins and pathways, which inhibits the development and progression of Alzheimer’s disease (AD) pathology and preserves cognitive function during aging.
REST
REST/MAP2
Legend: REST expression (green) is low in the cortex and hippocampus of young individuals (neurons are labeled with MAP2 in red). In cognitively intact (CI) aged individuals, REST is induced as amyloid beta and abnormally phosphorylated tau begin to accumulate. However, in CI aged individuals with extensive Alzheimer’s disease (AD) pathology, as well as in those with mild cognitive impairment (MCI) and AD, nuclear REST expression is lost. Biochemical and neuropathological analyses of post-mortem human brains, along with genetic studies in mice and primary neurons, demonstrate that this early induction of REST in CI aged individuals activates a neurodegeneration checkpoint that delays the onset and progression of AD pathology and cognitive decline.
The Yankner lab found that aging can be regulated by the excitation state of the nervous system, and that many different neuronal cell types influence lifespan in aging worms. They further demonstrated that neural excitation was subject to epigenetic regulation by the REST transcription factor, and that this mode of neural regulation was conserved from worms to humans. The highest levels of REST in the brain appeared in cognitively intact centenarians (Hyperlink to 2019 and 2022 papers:
C.elegans
Mouse
Legend: In C. elegans, the REST orthologues spr-4 and spr-3 are required for the extended lifespan observed in daf-2 mutants. Lifespan analyses were performed on wild-type (WT) worms, daf-2 loss-of-function mutants, and the indicated combinations of daf-2 and spr-4/spr-3 mutations. Loss of spr-4 or spr-3 significantly reduced the lifespan of daf-2 mutants, indicating their essential role in daf-2-mediated longevity. In mice, REST represses neuronal excitation in the brain. Top panel: PET–CT images of 18-month-old conditional REST knockout mice (REST⁻/⁻), in which REST was deleted from all neurons, show increased uptake of fluorodeoxyglucose (¹⁸F-FDG) compared to age-matched controls, indicating elevated neural activity. Lower panel: EEG recordings reveal increased epileptiform discharges in aged REST-deficient mice relative to controls, consistent with heightened neuronal excitability.
Taken together, the lab has identified a conserved mechanism of stress resistance and cognitive resilience, mediated by REST, that may prevent the onset of Alzheimer’s disease (AD) pathology and cognitive decline, while also enhancing cellular stress resistance that may contribute to delayed aging. REST may be one of several key resilience pathways that can be activated through physiological processes, lifestyle interventions, or pharmacological approaches.
Legend: Adaptive mechanisms that support stress resilience and brain function during aging operate on two levels: intrinsic physiologic processes (inner white circle) and those that can be activated through lifestyle or therapeutic interventions (outer light red ring). Intrinsic adaptive mechanisms include changes in neural networks, enhanced synaptic plasticity, reduced neural excitation, and broader systemic adaptations involving vascular function and circulating factors. Genetic influences, such as the protective APOE2 allele, may also engage or enhance these pathways. The outer ring represents adaptive responses that can be induced through behavior and treatment. Lifestyle factors—such as diet, physical activity, caloric restriction, cognitive stimulation, education, meditation, social engagement, and sleep—can recruit physiologic resilience mechanisms. Pharmacologic and therapeutic interventions aim to modulate metabolic, neuroprotective, and inflammatory pathways. Other strategies specifically target senescent cells, vascular health, or directly stimulate cognitive function in the aging brain.