{"id":2888,"date":"2025-10-03T16:08:11","date_gmt":"2025-10-03T20:08:11","guid":{"rendered":"https:\/\/haidut.me\/?p=2888"},"modified":"2025-10-03T16:08:11","modified_gmt":"2025-10-03T20:08:11","slug":"wasting-syndrome-cachexia-driven-by-low-metabolism-nad-can-be-blocked-reversed","status":"publish","type":"post","link":"https:\/\/haidut.me\/?p=2888","title":{"rendered":"Wasting syndrome (cachexia) driven by low metabolism\/NAD+; can be blocked\/reversed"},"content":{"rendered":"<p>One of those articles that fully corroborates Ray&#8217;s views that metabolism is central not only to &#8220;function&#8221;, but to structure as well, and also provides direct support that pro-metabolic measures can be life-saving. The wasting phenotype, most commonly seen in cancer, untreated diabetes I, and various mitochondrial pathologies has baffled medicine for a long time. Many remedies have been tried, with limited success. Anabolic steroids have so been the only somewhat reliable clinical intervention. Also, inflammation certainly plays a role and it has been shown that anti-inflammatory drugs are directly anabolic for critically ill or very old people, who all exhibit various forms of cachexia. However, the benefit is limited, showing that either inflammation is not the sole cause or that it is a downstream effect of a more general\/systemic process. The study below demonstrates that cancer induces a dramatic drop in oxidative metabolism (OXPHOS), with concomitant depletion of mitochondrial NAD+. The drop in OXPHOS and NAD+ are likely driven by chronic inflammation, which again implicates PUFA and various other environmental factors. The drop in mitochondrial NAD+ is directly caused by the fact that NAD+ is regenerated from the reduced form NADH through the Krebs Cycle and electron transport chain (ETC), which combined constitute what is commonly known as OXPHOS. Cancer cells produce a lot of NAD+, but it is only in the cytosol and comes at the expense of producing a lot of lactate (by using pyruvate as emergency oxidizing agent). Without OXPHOS, which happens only in the mitochondria, cancer cells cannot regenerate NAD+ oxidatively. The study below demonstrates that the inhibition of OXPHOS and the drop in mitochondrial NAD+ are not only core symptoms of cancer, but are also the main causes of cachexia (which is the dominant cause of death in such patients). Conversely, blocking pathways that result in NAD+ consumption, it is possible to elevate mitochondrial NAD+ and block the cachexia phenotype. That means something as simple as a combination of niacinamide and an oxidizing agent such as methylene blue, CoQ10, vitamin K, emodin, etc may be sufficient to not only block the cachexia, but also reverse the cancer process altogether.<\/p>\n<p><a href=\"https:\/\/doi.org\/10.1016\/j.molmet.2020.101046\">https:\/\/doi.org\/10.1016\/j.molmet.2020.101046<\/a><\/p>\n<p>&#8220;&#8230;<span style=\"text-decoration: underline;\"><strong><a class=\"topic-link\" title=\"Learn more about Cancer cachexia from ScienceDirect's AI-generated Topic Pages\" href=\"https:\/\/www.sciencedirect.com\/topics\/agricultural-and-biological-sciences\/cachexia\">Cancer cachexia<\/a>\u00a0and muscle loss are associated with increased morbidity and mortality<\/strong><\/span>. In preclinical\u00a0<a class=\"topic-link\" title=\"Learn more about animal models from ScienceDirect's AI-generated Topic Pages\" href=\"https:\/\/www.sciencedirect.com\/topics\/biochemistry-genetics-and-molecular-biology\/animal-model\">animal models<\/a>, blocking\u00a0<a class=\"topic-link\" title=\"Learn more about activin receptor from ScienceDirect's AI-generated Topic Pages\" href=\"https:\/\/www.sciencedirect.com\/topics\/medicine-and-dentistry\/activin-receptor\">activin receptor<\/a>\u00a0(ACVR) ligands has improved survival and prevented\u00a0<a class=\"topic-link\" title=\"Learn more about muscle wasting from ScienceDirect's AI-generated Topic Pages\" href=\"https:\/\/www.sciencedirect.com\/topics\/medicine-and-dentistry\/muscle-atrophy\">muscle wasting<\/a>\u00a0in cancer cachexia without an effect on tumour growth. However, the underlying mechanisms are poorly understood. This study aimed to identify cancer cachexia and soluble ACVR (sACVR) administration-evoked changes in muscle\u00a0<a class=\"topic-link\" title=\"Learn more about proteome from ScienceDirect's AI-generated Topic Pages\" href=\"https:\/\/www.sciencedirect.com\/topics\/biochemistry-genetics-and-molecular-biology\/proteome\">proteome<\/a>.<\/p>\n<div id=\"abssec0015\">\n<div id=\"abspara0015\" class=\"u-margin-s-bottom\">Healthy and\u00a0<a class=\"topic-link\" title=\"Learn more about C26 from ScienceDirect's AI-generated Topic Pages\" href=\"https:\/\/www.sciencedirect.com\/topics\/pharmacology-toxicology-and-pharmaceutical-science\/carcinoma\">C26<\/a>\u00a0tumour-bearing (TB)\u00a0<a class=\"topic-link\" title=\"Learn more about mice from ScienceDirect's AI-generated Topic Pages\" href=\"https:\/\/www.sciencedirect.com\/topics\/agricultural-and-biological-sciences\/mouse\">mice<\/a>\u00a0were treated with recombinant sACVR. The sACVR or PBS control were administered either prior to the tumour formation or by continued administration before and after tumour formation. Muscles were analysed by quantitative\u00a0<a class=\"topic-link\" title=\"Learn more about proteomics from ScienceDirect's AI-generated Topic Pages\" href=\"https:\/\/www.sciencedirect.com\/topics\/medicine-and-dentistry\/proteomics\">proteomics<\/a>\u00a0with further examination of mitochondria and\u00a0<a class=\"topic-link\" title=\"Learn more about nicotinamide from ScienceDirect's AI-generated Topic Pages\" href=\"https:\/\/www.sciencedirect.com\/topics\/biochemistry-genetics-and-molecular-biology\/nicotinamide\">nicotinamide<\/a>\u00a0adenine dinucleotide (NAD<sup>+<\/sup>) metabolism. To complement the first prophylactic experiment, sACVR (or PBS) was injected as a treatment after\u00a0<a class=\"topic-link\" title=\"Learn more about tumour cell inoculation from ScienceDirect's AI-generated Topic Pages\" href=\"https:\/\/www.sciencedirect.com\/topics\/medicine-and-dentistry\/tumor-cell-inoculation\">tumour cell inoculation<\/a>.<\/div>\n<\/div>\n<div id=\"abssec0020\">\n<div id=\"abspara0020\" class=\"u-margin-s-bottom\">Muscle\u00a0<a class=\"topic-link\" title=\"Learn more about proteomics from ScienceDirect's AI-generated Topic Pages\" href=\"https:\/\/www.sciencedirect.com\/topics\/biochemistry-genetics-and-molecular-biology\/proteomics\">proteomics<\/a>\u00a0in <span style=\"text-decoration: underline; color: #ff0000;\"><strong>TB cachectic mice revealed downregulated signatures for mitochondrial\u00a0<a class=\"topic-link\" style=\"color: #ff0000; text-decoration: underline;\" title=\"Learn more about oxidative phosphorylation from ScienceDirect's AI-generated Topic Pages\" href=\"https:\/\/www.sciencedirect.com\/topics\/agricultural-and-biological-sciences\/oxidative-phosphorylation\">oxidative phosphorylation<\/a>\u00a0(OXPHOS)<\/strong><\/span> and increased\u00a0<a class=\"topic-link\" title=\"Learn more about acute phase response from ScienceDirect's AI-generated Topic Pages\" href=\"https:\/\/www.sciencedirect.com\/topics\/biochemistry-genetics-and-molecular-biology\/acute-phase-response\">acute phase response<\/a>\u00a0(APR). These were <span style=\"text-decoration: underline;\"><strong><span style=\"color: #ff0000; text-decoration: underline;\">accompanied by muscle NAD<sup>+<\/sup>\u00a0deficiency<\/span>, alterations in NAD<sup>+<\/sup>\u00a0<a class=\"topic-link\" title=\"Learn more about biosynthesis from ScienceDirect's AI-generated Topic Pages\" href=\"https:\/\/www.sciencedirect.com\/topics\/biochemistry-genetics-and-molecular-biology\/anabolism\">biosynthesis<\/a>\u00a0including\u00a0<a class=\"topic-link\" title=\"Learn more about downregulation from ScienceDirect's AI-generated Topic Pages\" href=\"https:\/\/www.sciencedirect.com\/topics\/biochemistry-genetics-and-molecular-biology\/downregulation\">downregulation<\/a>\u00a0of nicotinamide\u00a0<a class=\"topic-link\" title=\"Learn more about riboside from ScienceDirect's AI-generated Topic Pages\" href=\"https:\/\/www.sciencedirect.com\/topics\/biochemistry-genetics-and-molecular-biology\/riboside\">riboside<\/a>\u00a0kinase 2 (<em>Nrk2<\/em>), and decreased muscle\u00a0<a class=\"topic-link\" title=\"Learn more about protein synthesis from ScienceDirect's AI-generated Topic Pages\" href=\"https:\/\/www.sciencedirect.com\/topics\/agricultural-and-biological-sciences\/protein-synthesis\">protein synthesis<\/a><\/strong><\/span>. <span style=\"text-decoration: underline;\"><strong>The disturbances in NAD<sup>+<\/sup>\u00a0metabolism and\u00a0<a class=\"topic-link\" title=\"Learn more about protein synthesis from ScienceDirect's AI-generated Topic Pages\" href=\"https:\/\/www.sciencedirect.com\/topics\/biochemistry-genetics-and-molecular-biology\/protein-biosynthesis\">protein synthesis<\/a>\u00a0were rescued by treatment<\/strong><\/span> with sACVR. Across the whole\u00a0<a class=\"topic-link\" title=\"Learn more about proteome from ScienceDirect's AI-generated Topic Pages\" href=\"https:\/\/www.sciencedirect.com\/topics\/agricultural-and-biological-sciences\/proteome\">proteome<\/a>\u00a0and APR, in particular, Serpina3n represented the most upregulated protein and the strongest predictor of cachexia. However, the increase in Serpina3n expression was associated with increased inflammation rather than decreased muscle mass and\/or\u00a0<a class=\"topic-link\" title=\"Learn more about protein synthesis from ScienceDirect's AI-generated Topic Pages\" href=\"https:\/\/www.sciencedirect.com\/topics\/medicine-and-dentistry\/protein-synthesis\">protein synthesis<\/a>.<\/div>\n<\/div>\n<div id=\"abssec0025\">\n<div id=\"abspara0025\" class=\"u-margin-s-bottom\">We present evidence implicating <span style=\"text-decoration: underline;\"><strong>disturbed muscle mitochondrial OXPHOS proteome and NAD<sup>+<\/sup>\u00a0<a class=\"topic-link\" title=\"Learn more about homeostasis from ScienceDirect's AI-generated Topic Pages\" href=\"https:\/\/www.sciencedirect.com\/topics\/medicine-and-dentistry\/homeostasis\">homeostasis<\/a>\u00a0in\u00a0<a class=\"topic-link\" title=\"Learn more about experimental cancer from ScienceDirect's AI-generated Topic Pages\" href=\"https:\/\/www.sciencedirect.com\/topics\/medicine-and-dentistry\/experimental-neoplasm\">experimental cancer<\/a>\u00a0cachexia<\/strong><\/span>. Treatment of TB mice with a blocker of\u00a0<a class=\"topic-link\" title=\"Learn more about activin receptor from ScienceDirect's AI-generated Topic Pages\" href=\"https:\/\/www.sciencedirect.com\/topics\/biochemistry-genetics-and-molecular-biology\/activin-receptor\">activin receptor<\/a>\u00a0ligands <span style=\"text-decoration: underline;\"><strong>restores depleted muscle NAD<sup>+<\/sup>\u00a0and\u00a0<em>Nrk2<\/em>, as well as decreased muscle protein synthesis<\/strong><\/span>. These results indicate <span style=\"text-decoration: underline; color: #ff0000;\"><strong>putative new treatment therapies for cachexia<\/strong><\/span> and that although\u00a0<a class=\"topic-link\" title=\"Learn more about acute phase protein from ScienceDirect's AI-generated Topic Pages\" href=\"https:\/\/www.sciencedirect.com\/topics\/biochemistry-genetics-and-molecular-biology\/acute-phase-protein\">acute phase protein<\/a> Serpina3n may serve as a predictor of cachexia, <span style=\"text-decoration: underline;\"><strong>it more likely reflects a condition of elevated inflammation<\/strong><\/span>.&#8221;<\/div>\n<\/div>\n","protected":false},"excerpt":{"rendered":"<p>One of those articles that fully corroborates Ray&#8217;s views that metabolism is central not only to &#8220;function&#8221;,&#8230;<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[2],"tags":[1540,55,12,97,77,70,883,1651],"class_list":["post-2888","post","type-post","status-publish","format-standard","hentry","category-science","tag-cachexia","tag-cancer","tag-inflammation","tag-metabolism","tag-mitochondria","tag-nad","tag-oxphos","tag-wasting","wpcat-2-id"],"_links":{"self":[{"href":"https:\/\/haidut.me\/index.php?rest_route=\/wp\/v2\/posts\/2888","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/haidut.me\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/haidut.me\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/haidut.me\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/haidut.me\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=2888"}],"version-history":[{"count":1,"href":"https:\/\/haidut.me\/index.php?rest_route=\/wp\/v2\/posts\/2888\/revisions"}],"predecessor-version":[{"id":2889,"href":"https:\/\/haidut.me\/index.php?rest_route=\/wp\/v2\/posts\/2888\/revisions\/2889"}],"wp:attachment":[{"href":"https:\/\/haidut.me\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=2888"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/haidut.me\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=2888"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/haidut.me\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=2888"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}