See figure 1.<\/strong><\/p>\nShe pointed out that seven of these nine marks of aging are involved in Alzheimer\u2019s disease.\u00a0 Her interests focus on three: loss of proteostatis, deregulated nutrient sensing, and mitochondrial dysfunction.\u00a0 Here she will talk mainly about proteostasis.<\/p>\n
Proteostatis, or \u201cprotein homeostasis\u201d, involves all of protein metabolism, folding, cycling, degradation, and aggregation occurring in young, healthy cells and tissues \u2013 as described in Figure 3 of the article above.\u00a0 Dr. Cortes explained that aging causes a loss of proteostasis, such as decrease in production of protein chaperones and a decrease in appropriate protein degradation.\u00a0 This forces proteins into the \u201cmisfolding pathway\u201d.\u00a0 The accumulation of protein inclusions can be observed, especially in neurons.\u00a0 This occurs in several neurodegenerative diseases, including Huntington\u2019s, Parkinson\u2019s, and Alzheimer\u2019s disease.<\/p>\n
She observed that altering (\u201ctweeking\u201d) proteostasis in one tissue of the body can have effects in other, distant tissues.\u00a0 This was first observed in simple model organisms, such as worms and fruit flies.\u00a0 The signal transmitting these effects was found to be insulin-like peptides.<\/p>\n
Insulin-like peptides, also called insulin-like growth factors (IGFs), are proteins with high sequence similarity to insulin which cells use to communicate with one another and adapt to their environment.<\/p>\n
Dr. Cortes mentioned that these peptides seem to support healthy proteostatis and are associated with longevity, at least in these simple model organisms.<\/p>\n
What about in mammals?\u00a0 She reminded us that there are only two interventions known to delay aging phenotypes in all animals, including mammals: exercise and dietary restriction.\u00a0 While the exact mechanisms for these effects are unclear, both delay aging metabolic phenotypes, including the loss of proteostasis.<\/p>\n
One particular tissue, skeletal muscle (SM), is especially influential in secreting these types of signals and helping to maintain body-wide proteostasis. \u00a0Young, healthy, and active SM seems to benefit signaling via the mTOR, IIS, AMPK, PGC1\u03b1 pathways, for example.\u00a0 An increase in muscle bioenergetics can be observed, and skeletal muscle autophagy is often improved.\u00a0 In short, SM acts as an endocrine organ; it secretes signals called myokines (skeletal muscle hormones) to communicate with other organs and organ systems, such as the liver, pancreas, and adipose tissues.<\/p>\n
To test this link between muscles and other organs, especially the brain, Dr. Cortes focused on transcription factor EB (TFEB), which regulates lysosomal function and autophagy.<\/p>\n
For those unfamiliar with this molecule:<\/p>\n
Lysosomes are bubble-like organelles in the cell cytoplasm containing degradative enzymes.\u00a0 They are a part of the cell\u2019s waste disposal system, whereby compounds taken up by endocytosis or autophagy are broken down.<\/p>\n
TFEB is called \u201ca master gene for lysosomal biogenesis\u201d.\u00a0 It controls the production of lysosomal hydrolases, membrane proteins and genes involved in autophagy.<\/p>\n
When the cell is starving or in certain diseased states, TFEB migrates from the cytoplasm to the nucleus, resulting in the activation of many target genes.<\/p>\n
Higher TFEB production usually results in more lysosomes being produced and more autophagy.<\/p>\n
When researchers \u201coverexpress\u201d TFEB overexpression in cells and mouse models of \u00a0Huntington\u2019s, Parkinson\u2019s, and Alzheimer\u2019s diseases, waste products are degraded the disease phenotypes are reduced.<\/p>\n
Dr. Cortes pointed out that when wild-type mice are starved TFEB expression is increased in skeletal muscle.\u00a0 She wondered if this change in SM could benefit the brain.<\/p>\n
First tests: +TFEB mice<\/strong><\/p>\nTo test this, she created a new mouse model which expressed the human TFEB gene \u201con demand\u201d, but only in SM. \u00a0This meant that TFEB protein levels would be 3-5x higher in the SM of these mice, when the system was triggered.<\/p>\n
She finds that this seems to increase autophagy, or rather cellular markers of autophagy, by ~20-30%.\u00a0 The normal age-related problems seen in aging mice, including the presence of aggregated proteins in SM tissues, did not occur in these +TFEB mice.<\/p>\n
An interesting note: Dr. Cortes pointed out that the protein aggregations and inclusions occurring in aging muscles also occur in skin cells, causing \u201cage spots\u201d.<\/p>\n
In short, +TFEB mice had muscles that seemed younger; they looked like 6-month old muscles instead of 16-month old muscles (the difference between young adult and aged mice). \u00a0It seems to prevent muscle aging.<\/p>\n
Cell metabolism was altered as well. In SM tissues +TFEB mice had:<\/p>\n
\n- \n
\n- higher levels of proteins involved, directly and indirectly, in mitochondrial oxidative phosphorylation (OXPHOS)<\/li>\n
- larger mitochondria<\/li>\n
- increased glucose processing and accumulation of glycogen<\/li>\n
- Higher levels of many enzymes involved in glycolysis<\/li>\n
- Improved OXPHOS capacity, which did not decrease with age (as it normally does)<\/li>\n
- Some myokine levels were increased<\/li>\n
- Some markers of inflammation (e.g., IL6) were reduced<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n
What about the brain?\u00a0 Were any of these benefits occurring in CNS tissue?<\/strong><\/p>\nYes, even though the +TFEB gene was only expressed in SM, some similar changes were observed in the brains of 18 month old mice.<\/p>\n
\n- \n
\n- Proteostasis proteins were more abundant.<\/li>\n
- Increases in mitochondrial autophagy were observed.<\/li>\n
- Improvements in lysosomal function \u2013 observed via the clearing of lipofuscin in lysosomes – were also noted.<\/li>\n
- Cognition was also improved in these +TFEB mice. Performance in Barnes maze and novel object recognition tests were improved.<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n
So, improved proteostasis in SM leads to better muscle health during aging, a \u201cyoung\u201d muscle secretome, neuroprotection, and better cognition later in life\u2026.at least for otherwise healthy mice.<\/p>\n
Second tests: does this help mice suffering from Alzheimer\u2019s disease-like pathologies?<\/strong><\/p>\nThere are reasons to believe it might.\u00a0 Skeletal muscle alteration is a reported characteristic of AD.\u00a0 Dr. Cortes noted that the disease is associated with lower muscle mass and function in older patients.\u00a0 Higher SM mass has been correlated with higher brain volumes during AD.\u00a0 And higher muscle mass in older patients is associated with a lower risk of developing AD.\u00a0 In mouse models of AD, exercise which caused the release of myokines \u2013 those circulating signals from muscle tissues – improve memory, as indicated in this 2019 article:<\/p>\n
Lourenco, M.V., Frozza, R.L., de Freitas, G.B. et al. Exercise-linked FNDC5\/irisin rescues synaptic plasticity and memory defects in Alzheimer\u2019s models. Nat Med 25, 165\u2013175 (2019). https:\/\/doi.org\/10.1038\/s41591-018-0275-4<\/p>\n
Dr. Cortes thinks that her +TFEB mice get the benefits of exercise without the actual exercise because of these circulating signals.\u00a0 To test this, she linked the circulatory systems of different strain of mice, by a surgical technique called parabiosis.<\/p>\n
Parabiosis is \u201cthe anatomical joining of two individuals, especially artificially in physiological research\u201d.<\/p>\n
Her group used mice that are models of AD (PS19 tau mice) and the previously mentioned +TFEB mice.\u00a0 These mice were connected, sharing blood and presumably the myokines, at the ages of 3-6 months, when the AD-like pathology of PS19 mice would normally develop.<\/p>\n
\n- PS19 mice developed the expected symptoms of AD.<\/li>\n
- But PS19 mice \u201cparabiosed\u201d \u2013 sharing a circulatory system \u2013 with +TFEB mice did not. Specifically, they had lower levels of p-tau and fewer \u201crogue\u201d microglia.<\/li>\n<\/ul>\n
The group is now examining global gene expression, specially of hippocampus tissue, for these animals.<\/p>\n","protected":false},"excerpt":{"rendered":"
Enhanced skeletal muscle as a novel determinant of CNS aging and Alzheimer\u2019s disease\u00a0 Alzheimer\u2019s Afternoons Seminar Series (April 21) Dr. Constanza J. Cortes, Brain Aging Physiology Lab, University…<\/p>\n","protected":false},"author":1263,"featured_media":1125,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[1],"tags":[],"class_list":["post-1123","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-uncategorized"],"_links":{"self":[{"href":"https:\/\/blogs.dickinson.edu\/arnoldt\/wp-json\/wp\/v2\/posts\/1123","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/blogs.dickinson.edu\/arnoldt\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/blogs.dickinson.edu\/arnoldt\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/blogs.dickinson.edu\/arnoldt\/wp-json\/wp\/v2\/users\/1263"}],"replies":[{"embeddable":true,"href":"https:\/\/blogs.dickinson.edu\/arnoldt\/wp-json\/wp\/v2\/comments?post=1123"}],"version-history":[{"count":0,"href":"https:\/\/blogs.dickinson.edu\/arnoldt\/wp-json\/wp\/v2\/posts\/1123\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/blogs.dickinson.edu\/arnoldt\/wp-json\/wp\/v2\/media\/1125"}],"wp:attachment":[{"href":"https:\/\/blogs.dickinson.edu\/arnoldt\/wp-json\/wp\/v2\/media?parent=1123"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/blogs.dickinson.edu\/arnoldt\/wp-json\/wp\/v2\/categories?post=1123"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/blogs.dickinson.edu\/arnoldt\/wp-json\/wp\/v2\/tags?post=1123"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}