Excess Lipids in Muscle Cells as a Contribution to Muscle Aging
Repair Biotechnologies, the company I co-founded, develops therapies based on the ability to selectively clear only excess cholesterol inside cells. This is normally an undruggable target. Cholesterol is essential to cell function, but expensive to manufacture. Species evolved a central factory for cholesterol production, the liver, and a complicated system of distribution that delivers cholesterol to and from the liver as needed. The vast majority of cells in the body neither manufacture nor break down cholesterol, but are completely dependent on it. Worse, too much cholesterol is toxic, and cells have little ability to deal with that toxicity when it occurs due to age-related or obesity-related dysregulation of cholesterol transport.
While Repair Biotechnologies focuses on reversal of atherosclerosis, an arguably equally important confirmation to come out of ongoing work at the company is that the presence of excess cholesterol inside cells - and likely other lipids as well - is an important contribution to age-related dysfunction in many tissues throughout the body. Whenever the Repair Biotechnologies scientists branch out to assess a new tissue in mice following treatment to clear intracellular cholesterol and see functional or structural improvement, that is a demonstration of the relevance of intracellular cholesterol to pathology in that tissue.
Thus it is always interesting to see some portions of the research community discussing the excess lipid issue with a focus on their specific tissue or organ of interest. Today's open access paper argues for the importance of excess cholesterol and other lipids in muscle cells. The infiltration of fat into muscle tissue with age and obesity is known to be a bad thing, but here the focus is more on the presence of excess lipids inside muscle cells and how that can be thought to contribute to the cellular dysfunctions that give rise to age-related loss of muscle mass and strength. The Repair Biotechnologies team has not assessed muscle tissue and muscle cells in any great detail to date, as this isn't on the roadmap to treating atherosclerosis, but perhaps they should.
Targeting intramyocellular lipids to improve aging muscle function
Decline of skeletal muscle function in old age is a significant contributor to reduced quality of life, risk of injury, comorbidity, and disability and even mortality. While this loss of muscle function has traditionally been attributed to sarcopenia (loss of muscle mass), it is now generally appreciated that factors other than mass play a significant role in age-related muscle weakness. One such factor gaining increased attention is the ectopic accumulation of lipids in skeletal muscle, in particular, intramyocellular lipids (IMCLs). It has been appreciated for some time that metabolic flexibility of several tissues/organs declines with age and may be related to accumulation of IMCLs in a "vicious cycle" whereby blunted metabolic flexibility promotes accumulation of IMCLs, which leases to lipotoxicity, which can then further impair metabolic flexibility.
The standard interventions for addressing lipid accumulation and muscle weakness remain diet (caloric restriction) and exercise. However, long-term compliance with both interventions in older adults is low, and in the case of caloric restriction, may be inappropriate for many older adults. Accordingly, it is important, from a public health standpoint, to pursue potential pharmacological strategies for improving muscle function. Because of the success of incretin-analog drugs in addressing obesity, these medications may potentially reduce IMCLs in aging muscles and thus improve metabolic flexibility and improve muscle health. A contrasting potential pharmacological strategy for addressing these issues might be to enhance energy provision to stimulate metabolism by increasing NAD + availability, which is known to decline with age and has been linked to reduced metabolic flexibility.
In this narrative review, we present information related to IMCL accumulation and metabolic flexibility in old age and how the two major lifestyle interventions, caloric restriction and exercise, can affect these factors. Finally, we discuss the potential benefits and risks of select pharmacologic interventions in older adults.
If intra cellular cholesterol get implicated as a cause of Alzheimer's disease or dementia, I hope you guys get some government money for research.
@Reason
are the any news from Repair Bio ? At the moment it seems one of the most promising companies in the anti-aging field ?
p.s.
It is frustrating to amusing how investors would pour money on some hooey like a years ago, casual games for facebook or blockchain, or everything that has "AI Agent" name on it now, but not even consider breakthrough bio/medical research. For a billionaire such an investment/donation might be the difference between life and death in a few years. Pocket change .... But go figure....
@ShellGhost: Generally, just keep up with news at https://www.repairbiotechnologies.com/ - those updates are what we can easily share.
@ShellGhost:
| go figure
Blame sedentary monoagriculture begot monogamy begot fear-of-death-by-aging patching through generational transmission of capital, for 10k years. I will never work for or associate with, in my fight to save myself from death-by-aging, with people who are not child-free or not couple-free.
Hello - mentioned in summary intro was most cells can't produce cholesterol. But this article in PubMed saying different. Please any more ideas or comments? Thanks
The pool of cholesterol is 2.2 mg/g body weight in the whole human body. Cholesterol is supplied by de novo biosynthesis and dietary intake. The contribution of de novo cholesterol synthesis and dietary intake to total cholesterol level in the body was estimated at a ratio of 70:30 [11]. The liver accounts for only 15% of de novo cholesterol synthesis, and up to 85% of cholesterol synthesis occurs in organs other than the liver [12].
Most organs and tissues meet their cholesterol requirements through endogenous cholesterol biosynthesis [13]. However, many cell types have mechanisms to absorb exogenous cholesterol sources in the form of plasma-derived lipoproteins [14]. All nucleated cells in the body can synthesize cholesterol from acetyl-CoA. Cholesterol biosynthesis is a complex biochemical process involving more than 30 different reactions using more than 15 different enzymes [15]. It consists of two paths: the Bloch pathway and the Kandutsch-Russell (K-R) pathway. These pathways are the two major post-squalene cholesterol biosynthetic pathways [16, 17]. The structure of cholesterol biosynthesis pathways is significantly different between tissues [18]. The reason why cells synthesize cholesterol through different routes is not well understood; some hypotheses have been proposed. In an experiment of genetically and environmentally controlled cholesterol formation, the flux of the K-R pathway remains relatively constant, but that of the Bloch pathway changes [19]. These results showed that, unlike the Bloch pathway, the K-R pathway can ensure a certain percentage of cholesterol synthesis with a subtle change in cholesterol requirements [18]. The Bloch pathway can be a method for the production of cholesterol depending on the surrounding environment. There have been some cases of cell type-specific implementation of these pathways. The skin, muscles, and heart contain more K-R pathway components than Bloch pathway components [20]. On the contrary, in the testis and adrenal gland, which require large amounts of cholesterol, the Bloch pathway is markedly active [18].
@Mike: That excerpt isn't correct in the proportions. The majority of cholesterol, 70-80%, is synthesized in the liver. A little is made in some other tissues, most of the rest comes from dietary sources. Cholesterol is scavenged from the intestines fairly aggressively, but to a first approximation synthesis is in the liver.