In our last article, we discussed how “Healthy Aging” is emerging as a new, targeted therapeutic area. Among the most surprising candidates showing promise in this field are glucagon-like peptide-1 receptor agonists (GLP-1 RAs) – medications originally developed to target diabetes. Research into GLP-1 RAs has an interesting history that started back in the early 1900s and involved the study of Gila monster venom. Joe Schwartz at the Montreal Gazette has a great article detailing the path to the discovery of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) and how they influenced insulin release after meals. Unfortunately, these peptide hormones persist in the bloodstream for only minutes in their native form, making them impractical as therapeutic agents. But further research led to the development of longer-acting peptides that mimic their mechanism of action. Labeled as a new class of drugs, called “incretin mimetics”, Eli Lilly’s Exenatide (Byetta®) was the first GLP-1RA to be approved by the FDA, as an add-on therapy for patients taking other forms of glucose-control medications, in 2005.

Over the last two decades, longer-acting formulations have been developed that eliminated the need for twice-daily injections. These advances improved dosing schedules from daily to weekly, with oral formulations now available as well. The research revealed an unexpected bonus: dramatic weight loss that is even more pronounced in people without Type 2 Diabetes [1]. Noting the side-benefit of weight loss from this new class of drugs, Liraglutide became the first FDA-approved GLP-1RA for obesity in 2014, and Semaglutide (Wegovy®) followed with approval in 2021. Beyond weight loss and glucose control, clinical trials are now showing benefits that extend beyond these two targets.

Not just Metabolic and Weight Control: GLP-1/GIP Benefits Healthspan

GLP-1 RAs work by mimicking a gut hormone that regulates blood sugar and appetite [2]. But robust clinical trial data now shows that these drugs also significantly reduce the risk of major cardiovascular events like heart attack and stroke, reducing mortality in patients with type 2 diabetes [3-6]. This benefit extends beyond what would be expected from weight loss or glucose control alone, suggesting a direct protective effect on the cardiovascular system.

In addition to their cardiovascular impacts, GLP-1 RAs have been shown to reduce liver fat buildup in non-alcoholic fatty liver disease (NAFLD) [7], and slow the progression of chronic kidney disease (CKD) in those with type 2 diabetes [8]. The FDA has already expanded approvals for semaglutide to include cardiovascular risk reduction and CKD protection, which are classic age-related conditions. This alone positions them as powerful “healthspan-extending” agents, and with newer, potentially more powerful classes of glucagon-modulating medications on the horizon, the future seems promising.

The triple receptor (GLP-1/GIP/GCG*) agonist retatrutide (not yet FDA-approved) not only demonstrated greater weight-loss efficacy over semaglutide in obese individuals without diabetes, but also improved outcomes in diabetic patients with steatotic liver disease (fatty liver). After 24 weeks of 12 mg retatrutide treatment, 86% of patients with type 2 diabetes and liver steatosis saw their liver fat return to healthy levels [9].

Targeting the Hallmarks of Aging

It has been generally accepted in the geroscience community that anti-aging drugs must target the fundamental “hallmarks of aging” [10], so where do GLP-1RAs fit in?

Hallmarks of Aging, (López-Otín et al., 2023. “Hallmarks of aging: An expanding universe“, Cell)

At present, these drugs target at least 4 hallmarks:

1. Reduces Chronic Inflammation: As we age, multiple systems become senescent and dysfunctional, and chronic, low-grade inflammation (aka “inflammaging”) sets in. This inflammaging is a key driver of age-related decline, including atherosclerosis, disc degeneration and arthritis [10]. GLP-1 agonists have demonstrated potent anti-inflammatory effects throughout the body [11], and recent preclinical studies show that this includes the brain [12].
2. Improves Mitochondrial Function:Another hallmark of aging is declining mitochondrial energy production. Mitochondria are the powerhouses of our cells, and when they lose their capacity to generate energy, multiple systems begin to fail. Symptoms of this decline start with fatigue, muscle weakness, and slower recovery, which can progress to organ dysfunction, neurological disorders and other age-related diseases [13]. Preclinical studies show that GLP-1 agonists can boost mitochondrial function, enhance cellular energy, and improve stress resistance [14, 15]. In humans, GLP-1 agonists have increased the number and improved the morphology of mitochondria, but further work is needed to determine if energy output is also improved [16].
3. Neuroprotection: Recent research has demonstrated that some GLP-1 agonists can cross the blood-brain barrier with the potential to protect against neuroinflammation and neurodegeneration [9, 10]. While exenatide did not improve symptoms of Parkinson’s disease (PD) in a recent study, lisixenatide, another GLP-1 RA that appears to cross the blood-brain barrier more readily, reduced symptoms in patients with early PD. Results from a large-scale multi-year study examining the impact of semaglutide on Alzheimer’s disease are expected soon [19].
4. Modulates Cellular Senescence: As we age, old and damaged cells can go into a zombie state, known as cellular senescence. These “zombie cells” linger and release a harmful cocktail of inflammatory signals that damage surrounding cells and tissues and contribute to inflammaging. Preclinical studies suggest that GLP-1 receptor activation may reduce DNA damage and accumulation of these aged “zombie cells” [20].

The Critical Caveats: Why They Aren’t a Fountain of Youth (Yet)

While excitement about the various potential disease targets for GLP-1 agonists is encouraging, it’s important to understand that these drugs are not without side-effects. Beyond the well-known side effects like gastrointestinal issues, pancreatitis, and hypotension, there are specific risks to consider from a longevity perspective, including:

• Sarcopenia: This is the most significant concern for a longevity drug. Sarcopenia is the progressive loss of muscle mass, strength and function which accompanies aging. Many studies confirmed that the rapid weight loss induced by GLP-1 agonists often includes a substantial loss of lean mass (up to 33% of weight loss can be attributed to loss of lean mass) and bone density [21]. For older adults, this can exacerbate frailty and increase the risk of falls and fractures, potentially negating any longevity benefits. To counteract the muscle loss associated with GLP-1RAs, researchers and drug companies are exploring combination treatments with antibody therapies [22, 23]. Early results from the COURAGE trial show that this approach not only preserved more than half the lean mass that would have been lost, but also enhanced overall fat loss.
• Thyroid Cancer: Recent research suggests that there may be a small increased risk of thyroid cancer in those treated with GLP-1 RAs. One study found risk was only increased in the first year of treatment, and suggested it might be due to increased thyroid screening (and thus earlier detection) [24], while another large international multisite study of over 98,000 GLP-1 RA users found no association [25]. Nevertheless, further research is needed to clarify the absolute risk.
• Mental Health: There are mixed reviews on the impact of GLP-1 RAs on mental health. Early clinical trials typically excluded those with a history of depression or suicidality, but a recent report in JAMA suggests that these medications should be prescribed with caution, particularly in patients who are currently taking benzodiazepines or antidepressants [26, 27].
• Unknown Long-Term Effects: There is currently no long-term safety data for using these powerful drugs in healthy, non-obese individuals for the sole purpose of extending lifespan.
• Mouse vs. Human: Preclinical studies in mice have demonstrated systemic impacts on aging parameters [20]. More recently, a study using low-dose GLP-1 RA treatment in older mice resulted in promising “aging rejuvenation” effects across multiple systems [28]. But as we all know, preclinical models do not always translate to humans [29]. More randomized controlled trials are required before we can make definitive statements about long-term benefits.

A Powerful Tool, But Not a Panacea

GLP-1 RAs are arguably the most compelling candidates for a “longevity-enhancing” drug to date, as they directly impact multiple core drivers of aging. Their ability to protect the heart, kidneys, and liver is undeniable. However, they are not a simple “anti-aging” pill, and the significant risk of muscle and bone loss presents a major hurdle that must be addressed. Further research is also needed to understand the neurological impacts of GLP-1 RAs. A key priority is to identify classes of GLP-1 RAs that can more effectively cross the blood-brain barrier.

GLP-1 RAs are not a cure for aging, but they ARE a groundbreaking class of drugs that are leading a paradigm shift in medicine. We are living longer now than we did at the start of this century, but we are also spending more time in poor health in our final years [30]. This class of drugs is rapidly moving from treating single diseases to targeting the aging process itself, with the promise of extending not just lifespan but more importantly, healthspan in our final decades.

*Acronyms: GIP, glucose-dependent insulinotropic polypeptide; GLP, glucagon-like peptide- 1; GCG, glucagon; JAMA, Journal of the American Medical Association; NAFLD, non-alcoholic fatty liver disease.

Disclaimer: The mention of specific companies, products, or organizations in this article is for informational purposes only and does not imply endorsement. The companies referenced were not consulted, involved in the preparation of this content, nor did they provide any funding or compensation.

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