Sirtuin Activation Therapy

Sinclair’s technology focused on activators of sirtuins. At the time its most famous was SRT-501, a proprietary resveratrol formulation.

Resveratrol and other sirtuin activators are believed to mimic the effects of calorie restriction. Although not entirely proven in humans, for animals – ranging from simple lifeforms like yeast to large mammals like dogs and rhesus monkeys – calorie restriction without malnutrition might be the one known thing which can slow down the aging process.

Rhesus monkeys are thought to be the most similar physiologically to humans, which is why they are so often used in medical studies. These photos are from a study conducted by the University of Wisconsin published in 2009 issue of Science Magazine (1). What makes this study so fascinating is that it’s been on-going since 1989.

regular vs. calorie restricted rhesus monkey

On the left is a 27.6 year old normal monkey (average lifespan for species). On the right is a monkey of the same age, but who has been on a calorie restrictive diet since an early age.

Those photos are worth more than a thousand words. While not studied for hair loss or male pattern baldness, it certainly should be!

Some studies have even found it be more effective than exercise at increasing life span. True, exercise protects against problems that reduce lifespan – like diabetes and heart disease – but only calorie restriction has been shown to slow primary aging (2).

The exact reason why is unknown. Researchers believe it may be due to the side effects of less free radicals being produced (and therefore less DNA damage), lower metabolic rates, lower core body temperature, and/or hormesis. Signalling molecules associated with aging including SIRT1, mTOR and PGC-1a are believed to be activated. Some wonder if a similar effect might be possible if we could find a way how to boost NAD levels.

Some compare calorie restriction to hibernation – the body, sensing a shortage of available food, goes into “conservation mode” to prolong life, to ensure it’s still alive for the future when times are better for reproduction.

What happened to resveratrol?

Before we review nicotinamide riboside (which is also sold under the brand name Niagen as a dietary supplement), let’s take a stroll down memory lane. Before the NAD supplement, it was all about resveratrol.

After Sinclair’s charismatic interview on 60 Minutesand the GlaxoSmithKline deal, resveratrol was all the rage during the late 00’s and early 10’s.

Red wine and grape juice – both of which only contain minuscule amounts of resveratrol – were being touted as a superfoods. Shady companies were peddling “one weird trick” to reverse the biological clock of aging. Some went so far as to claim it was the official Dr. Oz approved method (which was a lie, he does not sell or endorse supplements).

In 2013, GlaxoSmithKline gave pink slips to the 60 employees working in the Sirtris division, but continued carrying on some of that R&D under their corporate umbrella.

Here we are now almost a decade later. Nearly a billion dollars paid for sirtuins activators, but no drugs on the market. From excitement to silence.

Will Niagen follow a different path?

Fortune Magazine cover, Vol 155, No. 2.

 

 

 

 

 

 

 

 

 

 

 

So what happened to the resveratrol hype? Activating sirtuins to reverse aging (well, slow it anyway) doesn’t seem to be the debated topic. Rather, it’s that resveratrol and similar synthetic compounds might not be very effective at doing so in humans. Or if they are, they’re an inefficient method for doing so. Is it possible Niagen is more effective?

The fact that resveratrol has faded in popularity is not surprising, considering the suspected high doses needed and the fact that resveratrol (and presumably, similar compounds) are highly sensitive to degradation from light, heat, and air.

It’s one of the reasons we here at Superfoodly are mostly opposed to resveratrol supplements – just the air and light exposure from the manufacturing process alone results in degradation. Given the unscrupulous nature of many supplement marketers, it’s hard telling how much (if any) of the resveratrol powder or capsule is still in its ideal state.

For $5/month they might be worth the gamble, but they cost $50+ per bottle and even that amount may only yield 250 to 500 mg per day – a dosage that might be far too low to have any benefit, if there is any that’s possible. The dosage conversion of resveratrol milligrams per kilogram of body weight in animal models was often exponentially higher than what those resveratrol supplements offer you.

That being said, as per the words of one biotech insider here at Superfoodly, a billion dollars and one decade later with nothing to show is not that unusual in pharma. Will nicotinamide riboside follow the same path as the earlier generation of sirtuin activators and fade away? Or will it along with other future NAD+ supplements be the real deal?

Drugs take many years to develop and when an acquisition is shelved or put on the back burner, it doesn’t necessarily mean the science is lacking. Often times, it has more to do with prioritizing spending for shareholder return and choosing which drug candidates will produce revenue the fastest. Only GlaxoSmithKline truly knows how viable – or not – their portfolio of sirtuins activators might actually be.

In 2013 they claimed they were pursuing their lead candidate SRT2104 (GSK-2245840). There has been some activity, but not a lot.

graphs of SRT2104 in mice

The graphs pictured above are from research published in 2014 that was conducted under an agreement between GSK, National Institute on Aging (NIA) and the National Institutes of Health (NIH) (3). In other words, it’s unclear how much GSK was bankrolling that study, we’re guessing little to none given this statement on the cover page: This article is a U.S. Government work and is in the public domain in the USA.

Something more recent was published in 2015 with the title; “A Randomized, Placebo-Controlled Study of SRT2104, a SIRT1 Activator, in Patients with Moderate to Severe Psoriasis” (4)

There were 40 patients involved receiving either placebo or escalating doses of SRT2014. In terms of safety, both the drug and placebo groups experienced comparable side effects, which were said to be either mild or moderate.

SRT2104 resveratrol efficacy graph

As far as efficacy, based on skin biopsy analysis, 35% achieved “good or excellent” improvement while placebo was 5%. As you see in the graph, the higher the dosage, the more effective the treatment was.

That may sound great (and it is) but the problem is that even though it was published in 2015, the study was initiated in 2010 and last updated in 2012 (5). It’s not a recent study, they just took forever to publish the results.

What’s going on with resveratrol? The drugs? A look at the FDA’s clinical trials database shows that the last time there was any event for SRT2104 was on February 28, 2013, when they completed their phase 1b trial for ulcerative colitis (6). That has been discontinued/withdrawn, along with SRT2104 for plaque psoriasis, type 2 diabetes, cardiovascular disorders, inflammation, chronic obstructive pulmonary disease (COPD), and muscular atrophy.

Another aging clock – the 20 year lifespan of patents – hints that if the technology made commercial sense, they wouldn’t be dragging their feet, given that the IP protection won’t be good for much longer. Given the positive momentum that Niagen research has had this decade, perhaps GSK later realized that was the train they should have boarded instead.

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