By Prof. Gabriel A. Silva | 7 February 2022
Cognitive decline and forgetting things as we get older is almost a right of passage. All those ‘senior moments’ seem like an unavoidable part of life. Of course, as with most things, it is not binary. There exists a broad continuum that affects and impacts different individuals very differently, shaped by a complex interaction of genetic, environmental, and societal factors. For some there may be very little memory loss. Not much more than an occasional nuisance. While at the other extreme the loss of memory and related cognitive decline may be severe enough to be clinically impactful, such as with Alzheimer’s disease.
But why cognitive effects such as memory loss and aging go hand in hand is only recently beginning to be understood. One reason, it seems, is what scientists refer to as cellular senescence, essentially dormant cells stuck in a particular phase of the cell cycle. Still alive, but not doing much. The problem is they take up space, sort of speak, thereby affecting organ health and proper physiological function. In the brain this effect can block neuroregeneration. There is also accumulating scientific evidence that actively clearing them may reverse certain aspects of cognitive decline associated with aging, including memory loss.
What is cellular senescence?
Cellular senescence was discovered by Hayflick and Moorhead in 1961. It reflects a number of changes inside a cell that globally control cell fate and where the cell is in its lifecycle. Senescence is triggered by chemical cues and signals in response to different kinds of stress. Different cells types will respond differently, but the intensity and type of stress a cell experiences can cause it to respond by inducing processes that repair it, or can lead to cell death or senescence.
Cellular senescence: beneficial, harmful, and highly complexhttps://t.co/4fdjMxL7nc
— 🥼Agingdoc1⭐MD, PhD 🔔 (@agingdoc1) March 2, 2023
Cells may go into a state of senescence in response various triggers and stimuli that target changes in certain parts of its genetic machinery, changes in the pathways involved in cell division, or processes that affect the cell’s mitochondria, the organelles that provide cells with energy. It can also be caused by any number of pathologic or environmental stresses, such as oncogenic (cancer) activation, radiation, inflammation, nutrient deprivation, and exposure to different chemicals.
At the same time though, cellular senescence is not all bad. It evolved for a reason. There are a positive considerations the process brings to bear as well. For example, it is a mechanism that slows down and prevents the proliferation of cancer cells.
What cellular senescence does to the brain and memory
As senescent cells build up and accumulate in tissues and organs as we age — including the brain — they begin to affect important cellular and physiological functions. There is increasing data in animal model experiments that reducing the number of senescent cells via pharmacological or genetic approaches can reverse these physiological deficits and even extend lifespan. This includes the effects that neurodegeneration can have on the brain.
A number of studies have focused on senescent glial cells in the brain, an important and large class of non-neuronal cells that have a host of critical functions. There are about 85 billion neurons in the brain, but another roughly 86 billion non-neuronal cells. Microglia act as the brain’s immune cells, while oligodendrocytes are responsible for speeding up electrical signaling and communication in some neuron types. Astrocyte glial cells form a huge network onto themselves, independent of the neuronal network. They play critical roles in homeostasis, ensuring that the environment around neurons is conducive to proper brain health and efficient signaling. But they also seem to have the potential to both listen in and modulate neuronal communication and information processing directly.
— UCSD Engineering (@UCSDJacobs) July 17, 2021
Recent work has started to look at senescence in neural stem cells and related precursor cells that provide a pipeline to generate new neurons in key parts of the brain that are important for cognition. One of the areas neural stem cells in the fully developed brain of mammals reside is in a region called the subgranular zone in the hippocampal dentate gyrus. The hippocampus is a small but important structure deep within the brain that is critical for memory and learning. These neural stem cells in produce a class of neurons called dentate granule neurons that are important for memory formation and consolidation. The other major source of stem cells in the brain is the ventricular-subventricular zone that make olfactory bulb neurons that participate in the learning and discrimination of smells.
It is known that hippocampal neurogenesis — the formation and growth of new neurons in the hippocampus — and as a result hippocampus-dependent cognition drop off rapidly with age. These two events are coincident with a decrease in the production and activity of stem cells. But what is responsible for the decline of stem cell activity has remained an open question. In a research paper published just a few days ago from the University of Toronto, the authors of the paper showed that cellular senescence and accumulation of neural stem cells in the hippocampus of mice directly affect neurogenesis and hippocampus-dependent cognition. What’s more, they also provide evidence that pharmacologically removing the build up of senescent neural stem cells reverses cognitive decline. They used a drug called BT-263 (Navitoclax) which is known to induce the death (apoptosis) of senescent cells. The result was improved spatial memory when they tested the mice in a maze memory task.
Pharmacological ablation of senescent cells via acute systemic administration of the senolytic drug Navitoclax, caused a rapid increase in neural precursor cells proliferation and neurogenesis.https://t.co/3memV6No70
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As the authors conclude: “Aging is associated with an increase in senescent cells that disrupt tissue structure and function. Safe-in-human senolytics such as ABT-263 (Navitoclax), developed for the treatment of cancer, are therefore promising therapeutic agents to treat aging-associated conditions, with several in clinical trials to ablate senescent cells in osteoarthritis, diabetes complications, idiopathic pulmonary fibrosis, and chronic kidney disease. Our findings suggest that senolytics may also be considered for age-related cognitive decline.”
Reprinted with permission from the author.
Gabriel A. Silva is a theoretical and computational neuroscientist and bioengineer, Professor of Bioengineering at the Jacobs School of Engineering and Professor of Neurosciences in the School of Medicine at the University of California San Diego (UCSD). He is also the Founding Director of the Center for Engineered Natural Intelligence (CENI) at UCSD, and is a Jacobs Faculty Endowed Scholar in Engineering. He holds additional appointments in the Department of NanoEngineering, the BioCircuits Institute, the Neurosciences Graduate Program, Computational Neurobiology Program, and Institute for Neural Computation.
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