It’s easy to forget that selective androgen receptor modulators (SARMs) were initially developed for use in a medical context, and not as performance-enhancing substances. One exciting potential application is for treatment of Alzheimer’s Disease, a terrifying condition which appears to be modulated by the androgen receptors which SARMs target.
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What is Alzheimer’s
Alzheimer’s is one of the most terrifying diseases of the modern world, one of a number of conditions referred to under the broad umbrella of ‘dementia’ (from the Latin meaning, literally, ‘out of or removed from one’s mind’).
According to Alzheimer’s Disease International:
‘Someone in the world develops dementia every 3 seconds. There are over 50 million people worldwide living with dementia in 2020. This number will almost double every 20 years, reaching 82 million in 2030 and 152 million in 2050. Much of the increase will be in developing countries. Already 60% of people with dementia live in low and middle income countries, but by 2050 this will rise to 71%. The fastest growth in the elderly population is taking place in China, India, and their south Asian and western Pacific neighbours.’
The disease progresses through atrophy of the brain tissue. The early symptoms involve memory lapses, confusion and mood changes, which gradually worsen. As the disease progresses, a sufferer may experience extreme confusion, delusions and hallucinations, bouts of extreme anger and depression, as well as losing the ability to perform everyday tasks such as washing, eating, getting dressed or going to the toilet. By the onset of moderate to severe Alzheimer’s, the sufferer will almost certainly be a risk to their own safety and require round-the-clock care. Dysphagia (difficulty eating and swallowing), incontinence, weight loss and loss of speech are also common in the later stages.
As well as the serious physical and emotional cost of dementia for sufferers and their families, the social and economic cost – as much as it might seem distasteful to mix talk of extreme suffering and money – is enormous. Indeed, in many ways the physical and emotional suffering caused by the disease is made much worse by the massive social and economic costs.
Again according to Alzheimer’s Disease International, the global cost of dementia was 1% of global GDP in 2015, a figure that will only rise as more and more people succumb to the disease.
As the organisation explains:
‘This figure includes costs attributed to informal care (unpaid care provided by family and others), direct costs of social care (provided by community care professionals, and in residential home settings) and the direct costs of medical care (the costs of treating dementia and other conditions in primary and secondary care).
Direct medical care costs account for roughly 20% of global dementia costs, while direct social sector costs and informal care costs each account for roughly 40%. The relative contribution of informal care is greatest in the African regions and lowest in North America, Western Europe and some South American regions, while the reverse is true for social sector costs.’
If dementia were a country, it would be the 18th largest economy in the world…
Where SARMs Come into Play
Given the enormous costs of dementia, it’s not a surprise then that new treatments are being sought with great urgency. One of the most surprising potential treatments involves the use of SARMs, compounds which are now firmly associated with bodybuilders, athletes and people just looking to build muscle. Unbeknownst to many, SARMs were first developed for use in a medical context.
SARMs, or selective androgen receptor modulators, are a relatively new class of chemical compound most of which were initially developed for the purpose of aiding patients suffering from the effects of muscle and bone wastage. Muscle wastage, or cachexia, accompanies a wide variety of conditions, including cancer and its treatment, HIV, immobilization and glucocorticoid use. Bone wastage, or osteoporosis, may also be caused by some forms of cancer or cancer treatment, as well as dietary deficiencies and aging.
Because SARMs have been put to use by athletes as performance-enhancing drugs, it is easy to forget the original medical purpose for which these compounds were developed. The use of SARMs by athletes first became a concern around the Beijing Olympics in 2008, when the use of cardarine was flagged by authorities and a test was rapidly developed to detect its presence in an athlete’s urine.
Cardarine, a drug initially developed to treat metabolic diseases, promised serious increases in endurance and also fat loss capabilities, both of which promises have been borne out in clinical settings, in both animals and humans (see for instance these studies: one, two, three). Although cardarine is not technically a SARM – to use the technical term, it is a PPARδ agonist – it works in basically the same way as SARMs, by targeting specific receptor sites in the body, and is often used in conjunction with true SARMs as part of a ‘stack’.
Beijing 2008: when SARMs first came to prominence as performance enhancers in sport
SARMs induce anabolic activity – that is, growth – by directly stimulating the body’s androgen receptors, in particular. These are specific sites within the body to which androgenic (i.e. male) hormones, including testosterone and androsterone, bind.
The activity of these androgen receptors, and the binding of androgens to them, is crucial to the proper expression of male characteristics, including muscle growth and reproductive function. In the womb, androgens are responsible for sexual differentiation, and then during puberty they regulate the development and function of the penis, prostate and other sexual organs, as well as inducing growth spurts, larynx development and growth of skeletal muscle.
For adults, androgens regulate behaviour, the production of sperm, muscle growth, bone function and aspects of the cardiovascular system. Androgens regulate sexual function and are responsible, in part, for aggressive behaviour in men. As a result, disregulation or blocking of the androgen receptors can lead to a variety of conditions.
Clinical studies attest to the potential of SARMs to induce anabolic activity and reverse muscle loss and function. Animal trials have shown, for instance, that ostarine, a common SARM, can increase bone density and muscle mass, and these findings have been further confirmed in human trials.
Studies in humans have shown that even small doses of ostarine can lead to dramatically improved lean body mass and physical function among persons suffering from muscle wastage due to conditions such as sarcopenia and cancer (see for instance these studies: one, two, three). Studies of other SARMS, such as ligandrol, have replicated these effects (for instance this study). It should be noted that these human studies are studies of ordinary people, not elite athletes in competitive settings.
SARMs and Alzheimer’s: Why SARMs might work
It has been known for some time that Androgen depletion is a significant risk factor for Alzheimer’s disease. As one review article on SARMs explains:
‘Hypogonadal men [i.e. men with low testosterone] demonstrate a decrease in various cognitive processes, including episodic memory, working memory, processing speed, visual spatial processing and executive function. These functions are partially regulated by regions of the brain that are modulated by the AR [i.e. androgen receptors.]’
One study involved a sub-analysis of the Baltimore Longitudinal Study of Aging, which followed 407 men without dementia over a mean period of almost ten years. The sub-analysis, which considered the relationship between measured hormonal levels and the performance of the subject during a battery of physical and mental tests, showed that higher levels of free testosterone were associated ‘with better scores on visual and verbal memory, visuospatial functioning, visual-motor scanning and a reduced rate of longitudinal decline in visual memory’.
It has been shown that ‘circulating testosterone levels are inversely correlated with levels of Amyloid β(Aβ) in the brains of aged men.’ Aβ is an essential constituent of the plaques which form in the brains of people, and the SARM NEP28, like other androgens, has been shown to upregulate the expression of neprilysin, which works to degrade Aβ.
As the role of testosterone in cognition and brain health begins to be appreciated more and more, it is likely that SARMs could play a role in the treatment of dementia, as well as the other conditions, such as muscle wasting, for which the drugs were first developed. Their selectivity may prove to make SARMs very versatile indeed.
For more information on SARMs, check out our master article covering everything you need to know on SARMs.
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