Gabuzda D, Yankner BA.
Physiology: Inflammation links ageing to the brain.
Nature. 2013 May 1;
Please login to recommend the paper.
To make a comment you must login or register.
A Hypothalamus-Centric Inflammation-Mediated View of Aging. What About Energy Metabolism?
Zhang et al. (1) report three remarkable findings that transcend the fields of aging, neuroscience, and immunology. First, by selectively manipulating the activation state of the transcription factor NF-κB in cells of the mediobasal hypothalamus (MBH), they show that the lifespan of mice can be extended by reducing NF-κB activity and shortened by elevating NF-κB activity. Second, they provide evidence that a local microglia-mediated inflammatory process in the MBH drives aging of mice. Third, their data suggest that a local inflammation-mediated reduction in gonadotropin-releasing hormone (GnRH) is an important determinant of lifespan. As indicated in the title of their article, the authors’ overall conclusion from their findings is that inflammation-related processes in the hypothalamus program or coordinate the aging process throughout the entire animal. The notion that aging is a "programmed" process has been the subject of much debate in the aging field during the past half-century, with the current balance of evidence tipped in favor of aging not being programmed in most species, including mammals (2).
The hypothalamus clearly regulates the responses of many different organ systems to environmental conditions including energy (food) availability, stressors, and the presence of a potential mate. Among the functions of the hypothalamus, the one which would seem to be most likely to impact on the aging process is the regulation of energy metabolism. There is a strong rationale for the latter statement because of the extensive evidence that lifespan can be extended by reducing energy intake in a wide range of species, including mice, and the results of numerous studies in which signaling pathways are genetically manipulated point to pathways involved in cellular energy metabolism (e.g., insulin signaling and mTOR) in the aging process (3,4). Two unanswered questions, therefore, are if, and to what extent, the apparent effects of NF-κB and/or GnRH signaling on aging (1) are mediated by changes in the regulation of energy metabolism. In this regard, it is of interest to note that: 1) NF-κB regulates energy homeostasis (5); 2) GnRH neurons are regulated by glucose (6); and 3) obesity and type 2 diabetes (which shorten lifespan) inhibit GnRH production (7). It is, therefore, of great importance to rigorously evaluate energy metabolism in mice in which MBH NF-κB is manipulated.
Another major function of the hypothalamus is to coordinate adaptive responses of the organism to stress. NF-κB and TNF-α signaling play fundamental roles in cellular responses to local tissue injury/stress, and so it is reasonable that these stress-responsive proteins might also be involved in hypothalamus-mediated organismal stress responses. NF-κB and TNF-α signaling normally play important beneficial roles in developmental and synaptic plasticity, and in neuroprotection (8,9). Thus, TNF-α-NF-κB signaling induces the expression of the neurotrophic factor BDNF, the anti-apoptotic protein Bcl-2, the mitochondrial antioxidant enzyme Mn-SOD, and glutamate receptor subunits. During aging, and much more so in chronic inflammatory conditions, there occurs a dysregulation of TNF-α expression and NF-κB activity that adversely affects cellular functions, and may spread to cells and tissues beyond local sites where dysregulated inflammation is initiated. A general feature of aging that likely contributes greatly to cellular aging and associated diseases is a progressive impairment of adaptive cellular stress response mechanisms (10). For example, the ability of intermittent fasting (an "anti-aging" intervention) to induce the expression of neurotrophic factors, protein chaperones, and antioxidant enzymes in the brain is impaired during aging, and this is associated with dysregulated/chronic inflammation (11). It might, therefore, be the case that during aging the beneficial actions of NF-κB signaling are compromised, which then precipitates dysregulated inflammation. GnRH may normally enhance adaptive cellular stress responses, and a reduction in GnRH signaling during aging might, therefore, render cells more prone to oxidative stress and inflammation. Clearly, the intriguing findings of Zhang et al. raise many new questions regarding the interrelationships among inflammation, energy metabolism, and neuroendocrine signaling in the contexts of normal aging and age-related diseases.