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.
View the full article at FightAging
