Extending Average Human Lifespan Using Drugs

The trillion dollar opportunity to end obesity and metabolic disease

This should not come as a surprise: We are suffering, collectively, from an epidemic of obesity and metabolic syndrome. And it’s killing us.

This isn’t just limited to the US. Almost every country in the world (minus the notable exceptions of Germany and France) is continuing on a worryingly steep obesity trendline. Regardless of how many Sweetgreen and Equinox locations have opened up near you, and despite the growing popularity of the health and longevity-conscious movements, we are still getting fatter. This should worry you.

Obesity causes metabolic syndrome, a constellation of interrelated metabolic diseases that occur together and make each other worse.

Metabolic syndrome is the reason so many of us die from type II diabetes, cardiovascular disease, cerebrovascular disease, chronic kidney disease and fatty liver disease. It’s because all of these ailments egg each other on.

Addressing metabolic syndrome will not improve maximum human lifespan. The maximum human lifespan is currently ~120. However, solving metabolic syndrome very likely will radically extend average human lifespan.

Average vs Maximum Human Lifespan

Allow me to briefly draw a distinction between average human lifespan and maximum human lifespan.

The oldest person to have ever lived was Jeanne Calment, a French woman who died at the age of 122. The human body, with its current genomic design and under typical environmental conditions, can’t stretch much further than 120 years.

When most people think about drugs to extend human lifespan, they are thinking about supplements and pharmaceutical interventions that can help those of us who would otherwise die at age 60, get closer to Jeanne.

These kinds of drugs may increase healthspan and even delay death, but our body’s capacity to restore equilibrium to its myriad structural and biochemical systems still fades with time. Maximum human lifespan remains unchanged.

The Current Longevity Drugs

The approach thus far to developing longevity therapeutics has been to discover things that change with age, and to try to either supplement, preserve or degrade them. There are three main ways to do this.

Method 1

Conduct longitudinal biochemical analysis on serum and tissue samples to discover cell types or biomolecules that either deplete or accumulate over the course of mammalian lifespans, and then to either supplement those that decline or introduce compounds that break down/clear those that accumulate. Examples include:

• NAD+ Boosters: NAD+ is a coenzyme for hundreds of enzymes that facilitate redox reactions, and central to energy metabolism. The coenzyme directly and indirectly influences many key cellular functions, including metabolic pathways, DNA repair, chromatin modeling, cellular senescence and immune cell function. All of these processes are critical for maintaining tissue and metabolic homeostasis. However, levels of NAD+ decline with age, and this is causally linked to numerous aging-associated diseases, including cognitive decline, cancer, metabolic disease, sarcopenia and frailty. There is evidence that taking NAD+ boosters (NMN, TMG), can combat this decline by increasing production of the coenzyme, and that the restoration of NAD+ levels can promote human healthspan and lifespan.

• Sirtuin Activators: Sirtuins are a family of signalling proteins involved in metabolic regulation. Some, but not all of them are NAD+ dependent histone deacetylases, and others are protein deacetylases. These signalling proteins help protect against cellular stress and have been associated, albeit not without some controversy, with increased lifespan in some model organisms, like mice and fruit flies. At a cellular level, as NAD+ availability declines, sirtuin activity also decreases. Sirtuin activators like resveratrol have been found to interact with some sirtuin molecules (i.e. SIRT1) to promote their activity. However, there is now evidence that this activation is not direct, and only increases activity of SIRT1 towards certain substrates with bulky hydrophobic groups. That being said, the lifespan extension observed in mice and fruit flies is still promising. Time will tell if sirtuin activators can extend lifespan in humans.

• Glutathione Supplements: Glutathione is an endogenous antioxidant produced through enzymatic reactions in the pentose phosphate pathway (PPP), which is also responsible for NADPH production. Levels of glutathione decline with age, contributing to increased oxidative stress. Now we have supplements that aim to restore this antioxidant defense system.

• Senolytics: Senescent cells are cells that have stopped dividing but do not undergo apoptosis. These cells are abnormal in the sense that they are unable to proliferate owing to their stable cell-cycle arrest in the G1/G2 phase. This is a tumor-suppressive cell state, which is good. However, as senescent cells accumulate in tissues throughout the body, they contribute to the decline of our organ systems and secrete pro-inflammatory signals. Senolytics (e.g. Dasatinib and Quercetin) are compounds that attempt to target and clear senescent cells that accumulate with age.
  

Method 2

Study cellular processes and signalling that become dysfunctional over time, and to introduce molecules that attempt to preserve or enhance these cellular mechanisms into old age. Examples include:

• mTOR inhibitors: The mechanistic target of rapamycin (mTOR) is a central protein kinase that regulates cell growth, metabolism and survival in response to nutrients, growth factors and cellular energy status. Highly simplified, it responds to various growth cues (e.g. growth factors, hormones and high nutrient loads) in order to initiate anabolic processes, including nucleotide, lipid and protein synthesis, while inhibiting catabolic processes. Over time, mTOR signalling often becomes excessively active due to chronic exposure to growth factors and overnutrition. This leads to the promotion of cellular senescence, neurodegeneration, cancer and metabolic disease through the accumulation of damaged proteins, dysfunctional organelles (like mitochondria) and cellular debris. mTOR inhibitors (e.g. rapamycin and its analogs) primarily inhibit mTOR complex 1 (mTORC1). This mimics the effects of caloric restriction by downregulating protein and lipid synthesis and upregulating autophagy. This has been shown to clear senescent cells, improve metabolic health and increase lifespan in several organisms. The inhibition of mTORC1 also leads to activation of AMPK, which acts as a cellular energy sensor, as well as PGC-1α, which orchestrates mitochondrial function and biogenesis. Indirect PGC-1α activation by rapamycin enhances mitochondrial function by increasing mitochondrial oxidative capacity and respiration rate while decreasing the production of mitochondrial reactive oxygen species. For this reason, mTOR inhibitors remain a promising longevity drug. Unfortunately, chronic mTOR inhibition leads to a sustained reduction in muscle protein synthesis, which can lead to muscle atrophy. It’s very important to cycle on and off mTOR inhibitors, and the timing of administration is crucial for minimizing this side effect. But even then, muscle wasting is an awful tradeoff for better metabolic health. Across 49 studies, muscle wasting has been associated with 1.3x higher mortality risks of all causes. It increases the risk of cardiovascular disease (RR = 1.29), cancer (RR = 1.14), respiratory disease (RR = 1.36) and is the number 1 cause of fatal falls in the elderly. This is why most active gym goers and resistance trainers, including myself, do not include rapamycin in their longevity stacks. Maintaining our muscle mass into our 80’s and 90’s is incredibly important if we hope to reach our personal longevity escape velocities.

• Metformin: Originally a diabetes medication, metformin modulates a number of proteins involved in energy sensing and metabolism. There are too many proteins to mention here, so I will only mention a few. For one, metformin activates AMPK. AMPK is a key energy sensor that is activated when cellular energy is low. It does this by sensing high levels of AMP relative to ATP, and promotes catabolic processes that generate ATP, such as glucose uptake and fatty acid oxidation. It also inhibits anabolic processes that consume ATP, such as lipid and protein synthesis. Metformin also indirectly inhibits mTOR signalling, thereby promoting autophagy. Finally, metformin, impacts mitochondrial function by inhibiting Complex 1 in the electron transport chain (ETC). This initially reduces ATP production, but ultimately promotes mitochondrial biogenesis and turnover, and reduces ETC-mediated production of reactive oxygen species. As a result of these functions, metformin is one of the most promising longevity therapeutics. There is evidence that long-term use of metformin delays the onset of age-related diseases and extends average lifespan.

• Coenzyme Q10 (CoQ10): Mitochondrial function declines with age, and leads to decreased cellular energy and increased oxidative stress. CoQ10, also known as ubiquinone, is a lipid soluble molecule found in almost all cell membranes, but is also an essential component of the mitochondrial electron transport chain (mETC), facilitating electron transfer between complexes I and II to complex III. CoQ10 levels directly affect the efficiency of the mETC and hence ATP synthesis. Adequate CoQ10 levels ensure optimal electron flow through the complexes, minimizing electron leakage and reactive oxygen species (ROS) production. By scavenging ROS, CoQ10 helps prevent mitochondrial DNA and proteins from oxidative damage, which prevents mitochondrial dysfunction. However, as you expected, the production of CoQ10 generally declines with age due to decreased activity of enzymes involved in its biosynthetic pathway. Aging cells also often produce more ROS, which leads to greater consumption of CoQ10. Studies in rodents and model organisms like C. elegans have shown that CoQ10 supplementation can extend lifespan and improve healthspan. And human studies have shown that CoQ10 supplementation both reduces mortality in about half of elderly patients with cardiovascular disease, and improves glycemic control in type II diabetes. And long-term CoQ10 supplementation, when combined with selenium, has been shown to improve health-related quality of life, and increase the number of days out of the hospital in elderly individuals. There are clearly metabolic and cardiovascular benefits to long-term supplementation, however direct lifespan extension in humans has not been proven yet.
  

Method 3

Examine the risk factors for all-cause mortality in the elderly, and then develop drugs that address these risk factors at the biomolecular level.

• Statins (e.g., Atorvastatin, Rosuvastatin): HMG-CoA reductase is the rate-limiting enzyme in the mevalonate pathway of cholesterol biosynthesis. Statins competitively inhibit this enzyme, reducing endogenous production of cholesterol, and particularly low-density lipoprotein cholesterol (LDL-C). Reduced intracellular cholesterol production leads to up-regulation of LDL receptor expression on the surface of hepatocytes, allowing enhanced clearance of circulating LDL-C from the bloodstream into the liver for metabolism. By reducing LDL-C cholesterol, statins slow the progression of atherosclerosis, stabilise existing atherosclerotic plaques against potential rupture and inhibit the platelet aggregation that leads to thrombus formation. This all leads to a reduction in cardiovascular disease risk, including a reduction in the incidence of myocardial infarction, stroke and peripheral arterial disease. Studies of patients with coronary artery disease show that statins lead to a 30% reduction in all-cause mortality, and a 42% reduction in cardiovascular disease mortality. Given that these are leading causes of mortality in the elderly, it is safe to say that statins probably delay death in high risk populations.

• Gastrointestinal Lipase Inhibitors (e.g., Orlistat): These drugs prevent fat absorption by binding to and inhibiting gastric and pancreatic lipases within the gastrointestinal tract. This inhibits the breakdown of fats into fatty acids that are small enough to cross the brush border membrane of the small intestine, which therefore inhibits fat absorption. The undigested fat then passes out of your body next time you have a bowel movement. This has the nice side effect of making your stools exceedingly stinky. But that’s better than being obese and metabolically unhealthy.

• Antihypertensive Agents (e.g. ACE Inhibitors and Beta-Blockers): Antihypertensive agents are a broad category encompassing everything from diuretics to calcium channel blockers, ACE inhibitors and beta blockers. Each class lowers blood pressure through distinct mechanisms, which are not relevant to discuss here. What is important to note is that hypertension places increased shear stress on arterial walls, leading to structural damage and endothelial injury. Endothelial dysfunction promotes inflammatory processes, and oxidative damage, which further impairs vascular function. This allows lipid infiltration (particularly LDL-C) through damaged endothelium. The accumulation of lipids and associated recruitment of inflammatory cells leads to the development of atherosclerotic plaques, which grow, calcify and eventually obstruct blood flow or rupture to cause thromboembolic infarction of organs. Since hypertension is a significant risk factor for cardiovascular events, stroke, and other age-related conditions, it makes sense that anti-hypertensive agents increase average lifespan in patients who have it.

• Hydroxymethylbutyrate (HMB): Muscle wasting, or sarcopenia is the progressive loss of muscle mass, strength and function that occurs over the course of your lifespan. From about the fourth decade of life, you will lose about 1% of muscle mass per year. By the time you reach your 70s or 80s, this loss compounds to severely impact your ability to maintain mobility, joint stability, balance and posture. This muscle loss directly leads to increased fall risk, and falls are the leading cause of fatal and non-fatal injuries among the elderly. They rank around 7th in terms of overall causes of death. Supplementation with HMB has been shown to reduce age-related muscle breakdown, especially when combined with resistance training in untrained older adults.

• Antiplatelet Agents (e.g. Low-Dose Aspirin): Antiplatelet agents inhibit platelet aggregation–a key step in the formation of arterial clots. The most ubiquitous member of this class is aspirin, which is more commonly known as an over-the-counter pain reliever. Aspirin irreversibly inhibits the COX-1 enzyme in platelets by acetylating a residue at the enzyme’s active site. Since platelets lack a nucleus and cannot generate new proteins or enzymes, this effect lasts the entire 7-10 day lifespan of a platelet cell. Endothelial cells can regenerate COX enzymes because they have nuclei, and thus low-dose aspirin selectively inhibits platelet COX-1 without significantly affecting endothelial COX-2, preserving prostacyclin production and thus maintaining vasodilation. This prevents COX-1 from catalysing the production of prostaglandin from arachadonic acid. Prostaglandin is the precursor of thromboxane A2 (TXA2), which is a potent promoter of platelet activation and aggregation. By reducing the synthesis of TXA2, aspirin inhibits platelet clumping. Thus, long-term low-dose aspirin administration reduces the risk of myocardial infarction by preventing clot formation in coronary arteries. The same effect applies to other arterial blockages that cause ischemic stroke and pulmonary embolism. The evidence that aspirin reduces the incidence of these fatal thrombotic events is conclusive. It reduces cardiovascular disease risk and therefore increases healthspan in at-risk populations, but it doesn’t fundamentally increase maximum human lifespan.

There Are No True Longevity Drugs

The core conclusion of the evidence around these “longevity drugs” is that there are no true longevity drugs, at least as of yet. There are no “longevity genes” we can activate to increase lifespan. And there are no “longevity proteins” we can activate or inhibit to increase lifespan, especially in already healthy people.

There are only two true underlying killers apart from congenital genetic diseases: overnutrition and entropy.

We can prevent overnutrition with exercise, caloric restriction, fasting, and drugs to modulate the way our body absorbs, processes and uses nutrients for energy and metabolism (i.e. lipase inhibitors, metformin, mTOR inhibitors, etc). We can also combat overnutrition after it has already happened by manipulating biochemical pathways and cellular processes (i.e. statins, aspirin, ACE inhibitors, etc) to address the downstream consequences of metabolic dysfunction, and to prevent cardiometabolic syndrome-related illnesses.

Metabolic engineering to combat overnutrition is what I will be discussing in the rest of this article. Preventing entropy will come in a future article. It’s much more complicated and requires the convergence of multiple exponential growth trends.

Metabolic Syndrome

Metabolic syndrome can be broken down into:

• Risk factors: Poor diet, a sedentary lifestyle, a family history of obesity and being emotionally distressed (aka chronic high cortisol). The most important factor here is overnutrition (a form of malnutrition) resulting from excessive intake of nutrients. Most people in developed countries are eating hyperpalatable foods that humans have not evolved to deal with. We are not able to properly regulate our nutrient intake in this environment of hyperabundance, particularly when confounded with the fact that we are living largely sedentary lifestyles and ingesting enormous quantities of “edible” seed oils, hydrogenated fats and sugars. Our survival mechanisms prompt us to store excess energy as fat when food is plentiful.

• Overnutrition = Calories in > calories out for a long time + constant spikes in insulin due to a high energy intake from processed and high-carb foods. All this leads to accumulation of visceral fat that impairs health (i.e. become overweight/obese). You continue to accumulate fat, at first imperceptibly slowly. You diet, lose some fat, then gain it back (and a little bit more), then diet, lose fat, and gain it back (plus a little extra), but the overall trend is up and to the right.

• To store the biomass of all this fat, your visceral fat cells undergo hypertrophy and hyperplasia (grow in size and number), and begin releasing free fatty acids and adipokines (e.g. leptin) into the blood.

• Leptin is supposed to communicate to the satiety region in your hypothalamus that you have sufficient long-term energy stores, and that you should stop eating. However, most of us continue to accumulate fat as a consequence of our obesogenic environment and choices. High leptin levels lead to downregulated transport mechanisms, limiting leptin’s access to the hypothalamus. The leptin transporter system becomes saturated, and pro-inflammatory cytokines interfere with leptin signalling pathways. This leads to leptin resistance, and the inability of your hypothalamus to suppress your appetite and activate adaptive thermogenesis. Hence, your body weight set-point increases, and you become polyphagic and recalcitrantly fat.

• Those same visceral fat cells (adipocytes) have reached their fatty acid uptake capacity and are now undergoing severe hypertrophy and hyperplasia. They become bloated and inflammatory, secreting pro-inflammatory cytokines (TNF-α, IL-6, etc) into the bloodstream.

• This chronic, hyper-inflammatory environment disrupts metabolic signalling and leads to serine phosphorylation of the intracellular domain of the insulin receptor. This prevents your insulin receptors from being able to respond to their primary ligand, insulin. Now you have peripheral insulin resistance.

• The β cells of your pancreas sense elevated glucose levels and upregulate insulin production. For the same amount of insulin that it used to release, your peripheral tissues (muscle and adipose tissue), are unable to take up enough glucose to maintain your blood sugar levels within the homeostatic range. You now have a pernicious spiral of elevated glucose levels, leading to elevated insulin secretion, leading to insulin resistance, leading to elevated glucose levels.

• This causes hyperinsulinemia and pancreatic β cell exhaustion, ultimately leading to uncontrolled high blood glucose levels (aka hyperglycemia), all hallmarks of type II diabetes.

• In addition to regulating glucose uptake, insulin also regulates fat metabolism. As your enlarged and dysfunctional adipocytes become resistant to insulin-mediated glucose uptake, they start to break down stored triglycerides into free fatty acids, and release even more free fatty acids into the bloodstream.

• High levels of free fatty acids overload the liver, promoting fat accumulation and increased vLDL production. Your liver begins accumulating ectopic lipids. This is the beginning of non-alcoholic fatty liver disease (NAFLD).

• The pro-inflammatory cytokines released by the adipocytes also lead to chronic inflammation, which leads to inappropriate central activation of the sympathetic nervous system. This, in turn, increases heart rate, which increases cardiac output, which, in turn, increases blood pressure.

• The uncontrolled hyperglycemia and high blood pressure leads to shear stress on the endothelial membranes of your blood vessels and glycation of the thin capillary basement membranes. This leads to damage to the microvasculature in your brain (causing neuropathy), in your eyes (causing retinopathy) and in your kidneys (causing nephropathy, and eventually chronic kidney disease).

• This endothelial dysfunction also extends to your macrovasculature. The endothelial membranes of your larger arteries and arterioles respond to chronic, low-level inflammation by becoming permeable, allowing lipids (particularly LDL-C cholesterol, triglyceride-rich lipoproteins, and lipoprotein a) to enter the arterial wall and accumulate in the sub-intimal space. The LDL particles become oxidised, and form fatty streaks beneath your blood vessels.

• The chronic inflammation from these oxidised fatty streaks stimulates the release of cytokines, and promotes further endothelial dysfunction, which leads to the expression of chemokines that attract macrophages to the site. These macrophages attempt to phagocytose the lipids and LDL particles in an attempt to get rid of them. But there’s too many of them. There’s too much LDL, too many fatty streaks, too much inflammation. Your macrophages become frustrated, turn into “foam cells” and accumulate in the subintimal space. This is an atherosclerotic plaque, which can expand over the course of months, years and decades to constrict blood flow. And when it bursts, it’s called a thromboembolism.

• It can happen in your brain, causing a stroke, in your coronary arteries, causing a myocardial infarction (aka a ‘heart attack’), in your lungs, causing a pulmonary embolism, and in plenty of other places in your body.

• Eventually, you either die from an acute cardiovascular event, from liver failure, heart failure, or kidney failure.

If you want a full picture, you can check out this mechanism I made during my med school days.

This is all to say, most of us are metabolically unhealthy. We are eating too much of the wrong things, not exercising enough and accumulating too much visceral fat. Most of us are on track to develop heart disease, diabetes, chronic kidney disease or fatty liver disease during our lifetime. This is a pretty big cause of death, even if we solve the root causes of aging. Hence, the global effort by big pharma and biotech startups to counteract metabolic syndrome is warranted.

However, the vast majority of drug development efforts have focused on alleviating the symptoms and downstream consequences of prolonged metabolic dysfunction. Most companies and researchers are focused on inhibiting or activating various biomolecules in the attempt to counteract the symptoms of disease that emerge from long-term overnutrition.

For example, much of historical drug discovery methods have involved looking at biochemical pathways that are elevated or hyper-activated in disease states, and then attempting to develop small molecules that can bind to receptors, proteins or enzymes involved in these pathways, and allosterically inhibit them.

Using this logic, we’ve developed beta blockers, calcium channel blockers, ACE inhibitors, statins, diuretics, metformin, PCSK9 inhibitors and antiplatelet agents. These are all, mostly, good for humanity. But clearly something needs to change. Drug development needs to focus on addressing root causes of disease, in order to prevent disease, not to alleviate symptoms once the horse has left the station.

It wasn’t until recently that we developed GLP-1 receptor agonists (better known by their brand names Ozempic and Wegovy). This class of drugs is unique in the sense that they actually attempt to address the upstream causes of metabolic syndrome.

Ozempic and the Rise of the GLP-1 Agonists

This is how GLP-1 receptor agonists work:

1. GLP-1 receptor agonists mimic the action of the endogenous hormone GLP-1. GLP-1 is an endogenous peptide hormone produced by the L-cells of the distal small intestine in response to nutrient ingestion – especially fats and carbohydrates.

2. By activating GLP-1 receptors, GLP-1 receptor agonists artificially enhance insulin secretion from beta cells and suppress glucagon secretion from alpha cells. By lowering glucagon, these drugs decrease gluconeogenesis and glycogenolysis in the liver, thus reducing hepatic glucose production. GLP-1 receptor agonists also delay gastric emptying by modulating vagus nerve activity, leading to slower absorption of nutrients and prolonging the feeling of fullness. The prolonged digestion reduces the rate of glucose absorption, and therefore reduces the amplitude of blood glucose spikes.

3. An important point to make is that unlike exogenous insulin administration and many other drug classes, the enhanced insulin secretion in patients who take GLP-1 receptor agonists is glucose-dependent. When these drugs bind to GLP-1 receptors on beta cells of the pancreas, they stimulate activity of adenylate cyclase, which increases levels of cyclic AMP (cAMP). Elevated cAMP enhances insulin gene expression and promotes insulin secretion only in the presence of elevated blood glucose levels. In other words, next time you eat a meal, your post-prandial blood glucose spike is tempered by elevated insulin secretion from your beta cells. If we were talking about exogenous insulin administration, you might be at risk of acute hypoglycemia, and worsening insulin resistance. However, in the context of reduced hepatic glucose production and tempered post-prandial blood glucose spikes due to delayed gastric emptying, insulin sensitivity gradually improves.

4. But most importantly, the GLP-1 receptor agonists act centrally in the hypothalamus in brain regions involved in appetite regulation. If you remember earlier, I mentioned that it was visceral fat accumulation in obesity that led to chronically elevated leptin secretion and eventually leptin resistance. Leptin is the primary way that adipose tissue communicates long-term energy stores to the brain. So leptin resistance means that the brain is no longer sensitive to this communication and hence unable to downregulate appetite accordingly.

5. By binding to GLP-1 receptors in the brain, GLP-1 agonists artificially enhance satiety signalling pathways, resulting in appetite suppression. In this way, this class of drugs acts almost at the level of the root causes of metabolic syndrome. You become less hungry, eat less, calories in < calories out, visceral fat is used for energy production, you experience considerable weight loss (mostly by losing a significant amount of visceral fat), your adipocytes stop releasing pro-inflammatory cytokines, low-level chronic inflammation resolves, insulin sensitivity partially recovers, ectopic lipid levels in your liver begin to deplete, serum triglycerides and LDL cholesterol levels go down, oxidative stress decreases, your endothelial function improves, the chronic activation of your sympathetic nervous system resolves, your blood pressure goes down, shear stress on the arterial walls returns to baseline and there is partial regression and stabilisation of your atherosclerotic plaques. You become metabolically well again.

This sounds incredible. It sounds almost too good to be true. It’s not. These drugs truly are amazing. So why isn’t everyone on them?

I recently spoke to an MD-PhD endocrinologist at UCSF, and asked him this same question. “Why isn’t everyone on them? Shouldn’t everyone be on them?”

“Well I certainly hope not! It’s a sad world to live in if everyone needs to be on Ozempic,” he retorted.

However, the unfortunate reality is that world is sad. Most people don’t have the self discipline to adhere to strict diet and exercise regimens for long enough to lose visceral fat and maintain the weight loss. And the truth is that the same leptin and insulin resistance we talked about earlier also shifts the hypothalamic body weight set-point, which makes obese people increasingly polyphagic, and means that weight loss is highly recalcitrant.

Most people should be on Ozempic.

So why aren’t they?

It’s Not That Easy.

GLP-1 receptor agonists have not cured metabolic syndrome.

15% of patients who try Ozempic fail to achieve any clinically significant weight loss. 30% of patients who take Ozempic for non-alcoholic fatty liver disease fail to achieve any resolution of underlying pathophysiology. A study published in Nature noted that 82 percent of participants taking a semaglutide drug reported adverse effects, generally mild to moderate.

The GLP-1 agonists class of drugs cause gastrointestinal upset, muscle wasting in the elderly and several other side effects associated with the on-target activity of mimicking the GLP-1 hormone. They are also (at least currently) mostly available by way of physician or self-administered weekly subcutaneous injection. About 20% of patients will fail to adhere to GLP-1 agonists precisely because of this mode of drug delivery.

The space is crowded with second and third generation GLP-1 receptor agonists in various stages of clinical development, some of which are orally bioavailable. There are also several clinical trials on combination therapy – that is pairing GLP-1 agonists with other drug classes, like metformin and PCSK9 inhibitors – to maximise therapeutic value while reducing side effects.

The GLP-1 receptor agonist class is also in various stages of clinical trials for dozens of other clinical indications. Which makes sense. A drug that reverses obesity will also relieve or reverse many other diseases associated with metabolic syndrome.

And yet, despite all of this progress, one third of Americans remain obese. The obesity epidemic persists. GLP-1 receptor agonists will not rid us of this scourge of metabolic ill-health.

This is not a class of drugs that all of us can take every day. The risk profile of Ozempic not conducive to a long-term use as a prophylactic, the mode of administration remains cumbersome, and the drug is at risk of bankrupting an already-broken American healthcare system.

We need new classes of drugs focused on various other – and currently neglected – metabolic pathways: cheaper, better tolerated, more effective drugs with minimal side effect profiles that can be taken orally by the entire population as a prophylactic to overnutrition and an obesogenic environment.

Herein lies the trillion dollar opportunity to end obesity and metabolic disease, to return the US workforce to its peak productivity, to unburden the taxpayer from a bankrupt federal healthcare system, and to help preserve America as the predominant global superpower.

Seriously. Drugs that combat metabolic syndrome will have far-reaching effects across every aspect of the economy.

This is the holy grail of metabolic engineering.