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Slowing Down Aging
Cell Metabolism
Previews Slowing Down Aging Katharina Meyer1 and Bruce A. Yankner1,* 1Department of Genetics, Harvard Medical School, Boston, MA 02115, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.cmet.2017.09.012
The hypothalamus plays a key role in coordinating the physiological changes that underlie mammalian aging. In a recent issue of Nature, Cai and colleagues (2017) shed new light on the mechanism of this effect by providing evidence that hypothalamic stem cells may regulate aging through the release of microRNAs in exosomes. Aging is a progressive loss of physiological function that can lead to a variety of degenerative disorders, such as diabetes, cardiovascular disease, and Alzheimer’s disease. A myriad of hypotheses have been put forth to explain the causes of aging, including DNA damage, telomere shortening, mitochondrial dysfunction, hormonal imbalance, chronic inflammation, and cellular senescence in both the nervous system and other organ systems. Given the systemic nature of aging, the hypothalamus, a brain region that links neuroendocrine function to physiology, has drawn attention as a possible orchestrator of the overall physiological decline (Chen et al., 2015; Dacks et al., 2013). Cai and colleagues recently offered a proof of principle by demonstrating a link between systemic aging and inflammation and hormone secretion in the hypothalamus (Zhang et al., 2013). However, the cellular components and molecular mechanisms were only partially elucidated. Now, Zhang et al. (2017) have identified a distinct population of hypothalamic stem cells and exosomal release from these cells as a contributor to systemic aging in mice (Zhang et al., 2017). The generation of new neurons in the adult mammalian brain can occur in the hippocampus and hypothalamus and is mediated by distinct neural stem cell populations. These neural stem cells decline in number in the aging hippocampus, resulting in reduced generation of new neurons (Lee et al., 2012b). However, the impact of aging on hypothalamic neural stem cells (htNSCs) and the role of these cells in the aging process has been unclear. Cai and colleagues addressed these issues through elegant manipulations of the hypothalamic stem cell population in the aging mouse. First,
they demonstrated an age-dependent, progressive loss of htNSCs in the mediobasal hypothalamus, a region that plays a key role in the regulation of neuroendocrine secretion. They then showed that reduced numbers of htNSCs in this region correlated closely with age-related physiological decline, including reductions in endurance, coordination, novel object recognition, and dermal thickness. To determine whether loss of htNSC plays a causal role in age-related physiological decline, Zhang et al. (2017) used an approach for specifically ablating htNSCs in the medial hypothalamus. They injected two different lentiviruses that express either herpes simplex virus thymidine kinase-1 (Hsv-TK1) or diphtheria toxin receptor (DTR) under the control of the stem cell promoter Sox2. Subsequent treatment with either ganciclovir or diphtheria toxin resulted in the death of htNSCs expressing TK1 or DTR, respectively, leading to an approximately 70% depletion of htNSCs without the depletion of other cell types. Ablation of htNSCs accelerated aging-related physiological changes, with effects on endurance, coordination, sociality, novel object recognition, and spatial memory acquisition. These age-related phenotypes could be delayed by replenishing the neural stem cell pool in the mediobasal hypothalamus with htNSCs from newborn mice. However, given the proinflammatory hypothalamic environment in aging mice, Cai and colleagues first had to engineer NF-kBresistant htNSCs by expressing a dominant-negative IkBa; expression of this construct markedly increased cell survival following injection. Interestingly, implantation of only htNSCs, but not astrocytes or mesenchymal stem cells, showed anti-aging effects, including extension of lifespan. These results suggest that
592 Cell Metabolism 26, October 3, 2017 ª 2017 Published by Elsevier Inc.
htNSCs may have a unique role in promoting longevity. Considering the rapid improvement and remarkable impact of a small population of stem cells on aging, the authors reasoned that the effects were likely to be mediated through endocrine function rather than neurogenesis. Moreover, they observed that the exosomal protein CD81 and granule-like structures were highly abundant in htNSCs, implying a potential role for secretion of macromolecules in exosomes. They then isolated secreted exosomes from in vitro cultures of htNSCs and showed that these contain a broad complement of microRNAs. In addition, the number and identity of microRNAs in exosomes derived from htNSCs were quite different than those in exosomes derived from hippocampal neural stem cells, suggesting neuroanatomical specificity. In addition, a subset of 20 exosomal miRNAs from htNSCs was substantially decreased during aging in the mouse brain. Importantly, inhibition of exosome release from htNSCs led to age-related physiological impairment, which mimicked that observed following cellular ablation of htNSCs. Conversely, injection of purified htNSC exosomes proximal to the hypothalamus reduced age-related physiological deficits. Moreover, treatment of mice in which htNSCs had been ablated with purified exosomes reduced the severity of the ensuing physiological deficits. This study provides compelling evidence of a role for htNSCs in the regulation of systemic aging and suggests that exosomal secretion is likely to be part of the mechanism. The content of exosomes can range from peptides and lipids to mRNA and microRNAs. Given that Zhang et al. (2017) did not experimentally address whether microRNAs alone can
Cell Metabolism
Previews mine whether exosomal microRNAs released from htNSCs affect this pathway, particularly the central NF-kB signaling cascade and GnRH release from hypothalamic neurons (Figure 1). Furthermore, it has previously been found that proliferation of htNSCs is responsive to diet (Lee et al., 2012a; Li et al., 2012). A high-fat diet reduces the number of htNSCs, whereas caloric restriction increases the population. It was also found that hypothalamic energy-homeostasis circuits undergo constant remodeling in response to diet (McNay et al., 2012). Thus, htNSCs might play a role in coordinating diet, energy metabolism, and aging. These findings raise many intriguing questions and open new avenues for future investigation. It will be of great interest to extend these studies to the human brain in order to ascertain whether htNSC homeostasis is involved in human aging and in the onset of age-related degenerative disorders, such as diabetes and Alzheimer’s disease. REFERENCES Chen, T.T., Maevsky, E.I., and Uchitel, M.L. (2015). Front. Endocrinol. (Lausanne) 6, 7.
Figure 1. Neural Stem Cells and Hypothalamic Control of Aging The hypothalamus contains neural stem cells (htNSC) that are lost during aging and can promote longevity when implanted. These stem cells release microRNA-containing exosomes that, when exogenously introduced into the hypothalamus, reduce physiological changes associated with aging. It was previously shown that stress associated with aging activates hypothalamic microglia and increases NF-kB signaling in neurons, which in turn lowers GnRH secretion, contributing to systemic aging. It is possible that release of microRNAs from stem cell exosomes blocks the activation of NF-kB in neurons and restores GnRH secretion. Loss of htNSCs during aging may therefore contribute to the inflammatory and systemic physiological changes that accompany aging.
ameliorate age-related physiological decline, it will be of interest to determine whether other exosomal components also contribute. Central questions are which proteins and pathways are targeted by the exosomal microRNAs released from htNSCs and exactly how these affect aging. Cai and colleagues previously
showed that the hypothalamus is affected by age-related inflammatory changes mediated by the interaction of microglia with neurons and NF-kB signaling. This results in reduced secretion of the peptide hormone GnRH, which may promote physiological decline during aging (Zhang et al., 2013). It will be of interest to deter-
Dacks, P.A., Moreno, C.L., Kim, E.S., Marcellino, B.K., and Mobbs, C.V. (2013). Front. Neuroendocrinol. 34, 95–106. Lee, D.A., Bedont, J.L., Pak, T., Wang, H., Song, J., Miranda-Angulo, A., Takiar, V., Charubhumi, V., Balordi, F., Takebayashi, H., et al. (2012a). Nat. Neurosci. 15, 700–702. Lee, S.W., Clemenson, G.D., and Gage, F.H. (2012b). Behav. Brain Res. 227, 497–507. Li, J., Tang, Y., and Cai, D. (2012). Nat. Cell Biol. 14, 999–1012. McNay, D.E.G., Brianc¸on, N., Kokoeva, M.V., Maratos-Flier, E., and Flier, J.S. (2012). J. Clin. Invest. 122, 142–152. Zhang, G., Li, J., Purkayastha, S., Tang, Y., Zhang, H., Yin, Y., Li, B., Liu, G., and Cai, D. (2013). Nature 497, 211–216. Zhang, Y., Kim, M.S., Jia, B., Yan, J., Zuniga-Hertz, J.P., Han, C., and Cai, D. (2017). Nature 548, 52–57.
Cell Metabolism 26, October 3, 2017 593
Previews Slowing Down Aging Katharina Meyer1 and Bruce A. Yankner1,* 1Department of Genetics, Harvard Medical School, Boston, MA 02115, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.cmet.2017.09.012
The hypothalamus plays a key role in coordinating the physiological changes that underlie mammalian aging. In a recent issue of Nature, Cai and colleagues (2017) shed new light on the mechanism of this effect by providing evidence that hypothalamic stem cells may regulate aging through the release of microRNAs in exosomes. Aging is a progressive loss of physiological function that can lead to a variety of degenerative disorders, such as diabetes, cardiovascular disease, and Alzheimer’s disease. A myriad of hypotheses have been put forth to explain the causes of aging, including DNA damage, telomere shortening, mitochondrial dysfunction, hormonal imbalance, chronic inflammation, and cellular senescence in both the nervous system and other organ systems. Given the systemic nature of aging, the hypothalamus, a brain region that links neuroendocrine function to physiology, has drawn attention as a possible orchestrator of the overall physiological decline (Chen et al., 2015; Dacks et al., 2013). Cai and colleagues recently offered a proof of principle by demonstrating a link between systemic aging and inflammation and hormone secretion in the hypothalamus (Zhang et al., 2013). However, the cellular components and molecular mechanisms were only partially elucidated. Now, Zhang et al. (2017) have identified a distinct population of hypothalamic stem cells and exosomal release from these cells as a contributor to systemic aging in mice (Zhang et al., 2017). The generation of new neurons in the adult mammalian brain can occur in the hippocampus and hypothalamus and is mediated by distinct neural stem cell populations. These neural stem cells decline in number in the aging hippocampus, resulting in reduced generation of new neurons (Lee et al., 2012b). However, the impact of aging on hypothalamic neural stem cells (htNSCs) and the role of these cells in the aging process has been unclear. Cai and colleagues addressed these issues through elegant manipulations of the hypothalamic stem cell population in the aging mouse. First,
they demonstrated an age-dependent, progressive loss of htNSCs in the mediobasal hypothalamus, a region that plays a key role in the regulation of neuroendocrine secretion. They then showed that reduced numbers of htNSCs in this region correlated closely with age-related physiological decline, including reductions in endurance, coordination, novel object recognition, and dermal thickness. To determine whether loss of htNSC plays a causal role in age-related physiological decline, Zhang et al. (2017) used an approach for specifically ablating htNSCs in the medial hypothalamus. They injected two different lentiviruses that express either herpes simplex virus thymidine kinase-1 (Hsv-TK1) or diphtheria toxin receptor (DTR) under the control of the stem cell promoter Sox2. Subsequent treatment with either ganciclovir or diphtheria toxin resulted in the death of htNSCs expressing TK1 or DTR, respectively, leading to an approximately 70% depletion of htNSCs without the depletion of other cell types. Ablation of htNSCs accelerated aging-related physiological changes, with effects on endurance, coordination, sociality, novel object recognition, and spatial memory acquisition. These age-related phenotypes could be delayed by replenishing the neural stem cell pool in the mediobasal hypothalamus with htNSCs from newborn mice. However, given the proinflammatory hypothalamic environment in aging mice, Cai and colleagues first had to engineer NF-kBresistant htNSCs by expressing a dominant-negative IkBa; expression of this construct markedly increased cell survival following injection. Interestingly, implantation of only htNSCs, but not astrocytes or mesenchymal stem cells, showed anti-aging effects, including extension of lifespan. These results suggest that
592 Cell Metabolism 26, October 3, 2017 ª 2017 Published by Elsevier Inc.
htNSCs may have a unique role in promoting longevity. Considering the rapid improvement and remarkable impact of a small population of stem cells on aging, the authors reasoned that the effects were likely to be mediated through endocrine function rather than neurogenesis. Moreover, they observed that the exosomal protein CD81 and granule-like structures were highly abundant in htNSCs, implying a potential role for secretion of macromolecules in exosomes. They then isolated secreted exosomes from in vitro cultures of htNSCs and showed that these contain a broad complement of microRNAs. In addition, the number and identity of microRNAs in exosomes derived from htNSCs were quite different than those in exosomes derived from hippocampal neural stem cells, suggesting neuroanatomical specificity. In addition, a subset of 20 exosomal miRNAs from htNSCs was substantially decreased during aging in the mouse brain. Importantly, inhibition of exosome release from htNSCs led to age-related physiological impairment, which mimicked that observed following cellular ablation of htNSCs. Conversely, injection of purified htNSC exosomes proximal to the hypothalamus reduced age-related physiological deficits. Moreover, treatment of mice in which htNSCs had been ablated with purified exosomes reduced the severity of the ensuing physiological deficits. This study provides compelling evidence of a role for htNSCs in the regulation of systemic aging and suggests that exosomal secretion is likely to be part of the mechanism. The content of exosomes can range from peptides and lipids to mRNA and microRNAs. Given that Zhang et al. (2017) did not experimentally address whether microRNAs alone can
Cell Metabolism
Previews mine whether exosomal microRNAs released from htNSCs affect this pathway, particularly the central NF-kB signaling cascade and GnRH release from hypothalamic neurons (Figure 1). Furthermore, it has previously been found that proliferation of htNSCs is responsive to diet (Lee et al., 2012a; Li et al., 2012). A high-fat diet reduces the number of htNSCs, whereas caloric restriction increases the population. It was also found that hypothalamic energy-homeostasis circuits undergo constant remodeling in response to diet (McNay et al., 2012). Thus, htNSCs might play a role in coordinating diet, energy metabolism, and aging. These findings raise many intriguing questions and open new avenues for future investigation. It will be of great interest to extend these studies to the human brain in order to ascertain whether htNSC homeostasis is involved in human aging and in the onset of age-related degenerative disorders, such as diabetes and Alzheimer’s disease. REFERENCES Chen, T.T., Maevsky, E.I., and Uchitel, M.L. (2015). Front. Endocrinol. (Lausanne) 6, 7.
Figure 1. Neural Stem Cells and Hypothalamic Control of Aging The hypothalamus contains neural stem cells (htNSC) that are lost during aging and can promote longevity when implanted. These stem cells release microRNA-containing exosomes that, when exogenously introduced into the hypothalamus, reduce physiological changes associated with aging. It was previously shown that stress associated with aging activates hypothalamic microglia and increases NF-kB signaling in neurons, which in turn lowers GnRH secretion, contributing to systemic aging. It is possible that release of microRNAs from stem cell exosomes blocks the activation of NF-kB in neurons and restores GnRH secretion. Loss of htNSCs during aging may therefore contribute to the inflammatory and systemic physiological changes that accompany aging.
ameliorate age-related physiological decline, it will be of interest to determine whether other exosomal components also contribute. Central questions are which proteins and pathways are targeted by the exosomal microRNAs released from htNSCs and exactly how these affect aging. Cai and colleagues previously
showed that the hypothalamus is affected by age-related inflammatory changes mediated by the interaction of microglia with neurons and NF-kB signaling. This results in reduced secretion of the peptide hormone GnRH, which may promote physiological decline during aging (Zhang et al., 2013). It will be of interest to deter-
Dacks, P.A., Moreno, C.L., Kim, E.S., Marcellino, B.K., and Mobbs, C.V. (2013). Front. Neuroendocrinol. 34, 95–106. Lee, D.A., Bedont, J.L., Pak, T., Wang, H., Song, J., Miranda-Angulo, A., Takiar, V., Charubhumi, V., Balordi, F., Takebayashi, H., et al. (2012a). Nat. Neurosci. 15, 700–702. Lee, S.W., Clemenson, G.D., and Gage, F.H. (2012b). Behav. Brain Res. 227, 497–507. Li, J., Tang, Y., and Cai, D. (2012). Nat. Cell Biol. 14, 999–1012. McNay, D.E.G., Brianc¸on, N., Kokoeva, M.V., Maratos-Flier, E., and Flier, J.S. (2012). J. Clin. Invest. 122, 142–152. Zhang, G., Li, J., Purkayastha, S., Tang, Y., Zhang, H., Yin, Y., Li, B., Liu, G., and Cai, D. (2013). Nature 497, 211–216. Zhang, Y., Kim, M.S., Jia, B., Yan, J., Zuniga-Hertz, J.P., Han, C., and Cai, D. (2017). Nature 548, 52–57.
Cell Metabolism 26, October 3, 2017 593