AGING

Natural killers of cognition

One of the mechanisms driving aging and neurodegenerative diseases is the accumulation of senescent cells, while their elimination mitigates age-related decline. A new report details how, with aging, changes in the dentate gyrus microenvironment lead to natural-killer-cell-mediated clearance of neurogenic senescent cells, resulting in cognitive decline.

Life expectancy worldwide is continuously rising. At the same time, living to an old age also increases the risk of developing chronic pathological conditions. Understanding the common mechanisms that drive age-related diseases is necessary to treat these conditions and extend health span. These mechanisms, including impairments in immune system activity and accumulation of senescent cells, are the focus of extensive research. However, do the same molecular and cellular players of aging perform similar functions in all tissues and cell types? Jin et al.1 report a new role of natural killer (NK) cells in promoting brain aging, underscoring that not all tissues age the same.

Accumulation of senescent cells in tissues is one of the hallmarks of aging and contributes to the development of age-related pathologies2. These senescent cells acquire a distinctive secretome that attracts immune cells and facilitate their removal by the immune system3. However, at advanced age, the clearance of senescent cells is impaired, leading to chronic ‘sterile’ inflammation that promotes tissue damage and deterioration of tissue structure and function4. Furthermore, elimination of senescent cells in mouse models limits tissue aging and in some models even extends lifespan5 (Fig. 1).

Fig. 1: Elimination of senescent cells in normal aging and in neurodegenerative diseases.
figure1

Senescent cells accumulate in tissues with age and at sites of age-related diseases. They secrete cytokines that affect the microenvironment by attracting immune cells, including NK cells. Depletion of senescent cells in peripheral tissues by NK cells and elimination of senescent oligodendrocytes or astrocytes in models of age-related neurodegenerative diseases limits the functional decline of the tissues and improves cognition. In striking contrast, elimination of senescent neuroblasts by NK cells during normal brain aging impairs normal brain functionality and cognition.

Several immune subsets have essential functions in the adult brain, contributing to neurogenesis and learning6,7. Jin et al.1 show that accumulation and activation of NK cells in the normal aging brain impairs neurogenesis (Fig. 1). Senescent neuroblast cells accumulate in the dentate gyrus with age and secrete interleukin-27, which promotes local expansion and activation of NK cells. The NK cells, in turn, eliminate senescent neuroblasts in a process that results in cognitive decline. Depletion of NK cells significantly improves cognitive function and synaptic plasticity in old mice. The study suggests that removal of NK cells from the brain may serve as a therapeutic target to improve cognition in aged individuals. However, why neuroblasts become senescent and whether this process can be prevented in the first place remains unclear.

Senescent cells also accumulate in age-related neurodegenerative diseases (Fig. 1). For instance, they accumulate in Parkinson’s and Alzheimer’s diseases, and their elimination in mouse models limits the development of these diseases8,9. In striking contrast to this positive effect of depletion of senescent cells in peripheral tissues and in models of neurodegenerative diseases, Jin et al.1 observe that elimination of senescent neuroblasts by activated NK cells in the dentate gyrus impairs cognition and hippocampal synaptic plasticity during normal aging. This striking dichotomy between senescent cells in the normal aging brain compared to neurodegenerative diseases or in the periphery can be explained by the nature of the cells that become senescent. While non-neuronal populations might contribute to the pool of senescent cells during neurodegenerative disease, neuroblasts are the main cell types acquiring senescent features during normal aging. These senescent cells are growth-arrested and display elevated expression of proinflammatory molecules and SA-β-gal activity10. It is not yet clear whether these senescence features are simply indicators of cellular aging and accumulation of DNA damage. However, neuroblasts mature into functional neurons11. Therefore, elimination of these cells, even in their senescent state, might impair neurogenesis and neuroplasticity in the aging brain.

The differences between the pathological conditions and normal aging are not simply limited to the nature of the cells becoming senescent. Similar mechanisms of interaction between senescent cells and the immune system might have dissimilar effects in different microenvironments. In the periphery, senescent cells undergo immune surveillance by both attracting and activating immune cells, including NK cells, to facilitate their clearance from tissues12. During aging, NK cell activity and cytotoxicity decline in the periphery, which contributes to the development of age-related pathologies and reduction in health and lifespan4. Activation of the peripheral immune system increases the elimination of senescent cells and limits tissue damage13 (Fig. 1). NK cells can also eliminate senescent cells in the brain in a distinct spatial pattern. Jin et al.1 show that NK cells accumulate locally in the aged dentate gyrus, but not in adjacent areas, and upregulate molecules involved in NK cell activation and cytotoxicity. Such expansion and activation are mediated by local factors and by senescent neuroblasts. Together, it seems that the neurogenic niche in the dentate gyrus creates a unique microenvironment that facilities the accumulation of NK cells and their deleterious effect on the aging brain.

One emerging strategy to extend health and longevity is to eliminate senescent cells using pharmacological compounds that can induce cell death in senescent cells, also known as ‘senolytics’14. Targeting senescent cells by senolytics have largely beneficial impacts in limiting age-related pathologies in peripheral organs2. Therefore, it is of interest to understand whether these approaches can be implemented in the context of age-related neurodegenerative diseases. In the light of the study by Jin et al.1 it would be necessary to strictly regulate which senescent cells are eliminated. The first distinction is between senescent cells in the periphery and in the CNS. This can be achieved by using senolytics that do not cross the blood–brain barrier (BBB). Such compounds will eliminate senescent cells only in the periphery, which should not deleteriously affect brain aging. On the contrary, it might support brain maintenance, helping to protect the CNS against injury or neurodegenerative disease15 (Fig. 1).

Finding the best candidates for targeting specific populations of senescent cells in the brain would be more challenging. This is not restricted to finding candidates that can be administered orally and cross the BBB. Senescent cells are a highly heterogeneous population with apparent cell-type-specific effects. Elimination of neurogenic senescent cells contributes to cognitive decline1, while elimination of senescent oligodendrocytes or astrocytes protects from development of neurodegenerative conditions8,9 (Fig. 1). Thus, it will be necessary to investigate the influence of every treatment on diverse cell populations and pathological conditions. Regardless, if senescent cells are indeed active drivers of neurodegeneration, treatment with designated senolytics that would spare neuroblasts could lead to the development of therapeutics to elevate these devastating diseases.

Overall, the effects of senescent cells are diverse and cell-type-specific. These cells accumulate with aging and in sites of neurodegenerative pathologies. Furthermore, these cells are linked to the etiology of these diseases, highlighting the detrimental role of senescent cells in aged individuals. On the other hand, Jin et al.1 report a novel insight into age-related changes in the neurogenic niche microenvironment that drive immune-mediated clearance of neurogenic senescent cells, leading to cognitive impairment. Further studies of senescent cells’ heterogeneity and their cell-type-specific properties will provide more insights into the biology of aging in general and age-related neurodegenerative disease in particular. They will also provide plausible strategies to treat these diseases and extend health span.

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Correspondence to Valery Krizhanovsky.

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V.K. is an author of patents in the field of senescence and senolytics.

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Papismadov, N., Krizhanovsky, V. Natural killers of cognition. Nat Neurosci 24, 2–4 (2021). https://doi.org/10.1038/s41593-020-00749-6

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