Mitochondrial uncoupling is the process by which mitochondria in cells switch from producing the chemical energy store molecule adenosine triphosphate (ATP) to releasing that energy as heat. This is of interest in the context of aging because upregulation of mitochondrial uncoupling via a range of strategies appears to somewhat slow aging in animal studies. Sustained upregulation of mitochondrial uncoupling also produces a reduction in fat tissue and weight loss. Humans being humans, there is considerably more interest in that outcome than in effects on aging, particularly now that weight loss drugs have become a large revenue source for the major pharma companies.
Historically, researchers have struggled to produce mitochondrial uncoupling drugs that will not kill people through overheating if taken at a high enough dose. One of the first such drugs to be developed and fairly widely used, back in the early 20th century, was 2,4-dinitrophenol (DNP). While there is very little literature on accidental deaths as a result of its use, it is certainly possible to take enough DNP to die from hyperthermia within a few days without any immediate sign that a fatal dose was ingested, and without any recourse once realization sets in. Any drug that directly upregulates uncoupling in the same way will likely have similar characteristics.
In today's research materials, the authors claim to have found a safe approach that bypasses the mechanism used by past approaches to upregulate uncoupling, meaning to influence the activity of uncoupling protein 1 (UCP1). In this approach, UCP1 is not involved in the switch from ATP generation to thermogenesis, and further the effect only occurs in adipose cells, not body-wide. Given present biases in funding and interest, the researchers of course pitch this as a strategy for weight loss, but it could be interesting in the context of aging as well.
Article presents innovative drug for controlling weight and blood sugar
The experimental drug, currently called SANA (short for "salicylate-based nitroalkene"), is a derivative of salicylate, a chemical compound with analgesic and anti-inflammatory properties found naturally in plants and used to make drugs such as aspirin (acetylsalicylic acid). Researchers initially sought to develop an anti-inflammatory drug. To this end, they tested several chemical modifications to the salicylate molecule. "We wanted the precursor used to be as safe as possible. Salicylate is the drug that's been known the longest, and many people consume its derivatives daily. However, we observed that instead of protecting against inflammation, the molecule we synthesized protects against diet-induced obesity."
Two different models were used to test this effect in animals. In the first model, SANA was administered to mice alongside a high-fat diet, which prevented any weight gain. Meanwhile, the animals in the control group gained between 40% and 50% of their body weight over eight weeks. In the second model, treatment began after the animals were obese. After three weeks, the mice had lost 20% of their body mass. There was also a reduction in blood sugar, improved insulin sensitivity, and a decrease in fat accumulated in the liver (a condition known as hepatic steatosis for which there is still no effective pharmacological treatment).
Experiments showed that SANA specifically targets adipose tissue, activating thermogenesis through an unconventional mechanism. It can therefore be considered the first in a new class of anti-obesity drugs. It does not affect the central nervous system or digestive system or appetite. Thermogenesis is typically mediated by a protein called UCP1, which is found within mitochondria. UCP1 is activated in certain situations, such as exposure to cold. It then interferes with the synthesis of ATP (adenosine triphosphate), the cellular fuel. This causes the energy generated by cellular respiration to dissipate as heat. However, this is not the case with SANA. The new drug causes adipocytes to use creatine, a compound formed by three amino acids (arginine, glycine, and methionine), as an energy source to produce heat without involving the UCP1 protein.
According to the researchers, the observed impact on body temperature is small and does not pose a significant health risk. "Older thermogenic agents, such as dinitrophenol, have an effect on the mitochondria of the entire body, causing a large increase in temperature and overloading the cardiovascular system, which needs to increase blood pressure for blood to reach the periphery and dissipate heat. But in the case of SANA, there's only action on the mitochondria of adipose tissue."
Through phenotypic drug discovery, we developed promising nitroalkene-containing small molecules for obesity-related metabolic dysfunctions. Here, we present SANA, a nitroalkene derivative of salicylate, demonstrating notable efficacy in preclinical models of diet-induced obesity. SANA reduces liver steatosis and insulin resistance by enhancing mitochondrial respiration and increasing creatine-dependent energy expenditure in adipose tissue, functioning effectively in thermoneutral conditions and independently of uncoupling protein 1 and AMPK activity.
Finally, we conducted a randomized, double-blind, placebo-controlled phase 1A/B clinical trial, which consisted of two parts, each with four arms: (A) single ascending doses (200-800 mg) in healthy lean volunteers; (B) multiple ascending doses (200-400 mg per day for 15 days) in healthy volunteers with overweight or obesity. The primary endpoint assessed safety and tolerability. Secondary and exploratory endpoints included pharmacokinetics, tolerability, body weight, and metabolic markers. SANA shows good safety and tolerability, and demonstrates beneficial effects on body weight and glucose management within 2 weeks of treatment.
View the full article at FightAging
