New Compound Added to Short List of Molecules Targeting Aging Process

By Deborah Borfitz

December 12, 2023 | The development of antibiotics for treating tuberculosis in the 1940s eventually closed the doors of high-altitude sanitoriums that had long been the best therapeutic option for millions of patients. In much the same way, researchers at the Buck Institute for Research on Aging hope to one day eliminate the need to admit people suffering from Alzheimer’s, Parkinson’s disease, and other age-related phenomena to a geriatric or psychiatric hospital. 

But it won’t happen until many more compounds are in the pipeline to bring an end to what is arguably a solvable problem. The premise behind research underway at the Buck is that aging is not only a risk factor for most major chronic diseases, but targeting the basic age-related processes across tissues will have an impact on several diseases as well as on aging itself, according to Gordon Lithgow, Ph.D., professor and vice president of academic affairs.

More than two decades ago, Lithgow coined the term “geroscience” to describe research on the mechanisms driving aging. The Buck Institute for Research on Aging was the recipient of a roadmap grant from the National Institutes of Health (NIH) that effectively coalesced geroscience as a distinct area of study.

For their part, the Buck team recently discovered a natural, drug-like compound that was found to extend lifespan in the nematode Caenorhabditis elegan, to ameliorate pathology in neurodegenerative disease models of the worms, and improve mitochondrial function in mouse muscle cells, as reported in Nature Aging (DOI: 10.1038/s43587-023-00524-9). Dubbed MIT (Mitophagy-Inducing Compound), it is a type of coumarin—molecules known to have vast therapeutic potential, which are naturally occurring in many plants and found in high concentrations in certain types of cinnamon. 

Mitochondrial dysfunction is one of the dozen hallmarks of aging and is also seen in the context of several age-related diseases, says Julie Andersen, Ph.D., a professor at Buck. It is consequently a major area of interest for many pharmaceutical companies. 

While the wider field of anti-aging medicine has been riddled with a lot of pseudo-science over the years, the Buck has painstakingly adhered to “hard-edged” science since its founding in 1999, says Lithgow. The latest project started in a mouse model of Parkinson’s disease in the Andersen lab. 

The model expressed a PRKN gene mutation known to be involved in mitophagy, the process by which defective mitochondria are eliminated from cells to ensure proper cellular functioning. Mitophagy goes awry both in normal aging and the neurons effected in Parkinson’s disease, says Andersen. Defective mitophagy also plays a role in cardiovascular diseases such as heart failure, influences metabolic disorders that include obesity and type 2 diabetes, is implicated in muscle wasting and sarcopenia, and has a complex relationship with cancer progression. 

A mouse study out of the University of California, Los Angeles, found an age-related reduction in nerve cells in the mid-brain region, “the same ones that tend to be blocked in human [Parkinson’s] patients ... [thanks to] a buildup of this protein called alpha-synuclein,” she continues. Using a mouse model of the disease, the Anderson lab showed that the functional deficits of those phenotypes are due to a defect in the mitophagy-driven byway. 

Treating the mice with rapamycin—the first small molecule shown to extend lifespan in the preclinical setting—independently revved up mitophagy and prevented neuropathology, including loss of motor function, reports Andersen. A research scientist in her lab, Shankar Chinta, decided to go looking for other small molecules that might enhance mitochondrial turnover and after screening a million neuronal cells against a natural drug library, MIC turned up as a major hit. 

This sort of work is the forte of the Buck, she says, noting that Lithgow heads up the NIH Caenorhabditis Intervention Testing Program that actively screens small molecules for lifespan extension in worms. These are often taken into disease and animal models of Parkinson’s and Alzheimer’s disease, which has proven to be an effective means of identifying candidate agents—including some now in clinical studies based on findings coming out of Buck. 

Gut-Brain Connection

Andersen’s interest is neurodegeneration, but the fact that MIC also extends lifespan exemplifies the tenet of geroscience that aging is the underlying cause shared by all age-related diseases, she says. It falls in a class of compounds known to enhance the expression of transcription factor EB (TFEB), an identified master regulator of autophagy and mitochondrial function. 

TFEB therefore turns on a lot of genes involved in liposomal function, which decreases with age, Andersen notes. Liposomes are sacs of enzymes responsible for breaking down defective proteins and mitochondria. 

Most of the small molecules found to act on TFEB, including rapamycin, do so via the phosphorylation mechanism, she says. MIC instead works as a transcriptional inducer of mitophagy through helix-loop-helix protein 30 (HLH-30)/TFEB. 

As covered in the Nature Aging paper first-authored by Buck research scientist Manish Chamoli, Ph.D., MIC was found to effectively enhance lysosomal function, induce mitophagy, and improve mitochondrial function. Importantly, he says, the activity of HLH-30/TFEB is controlled by the nuclear hormone receptor that is called DAF-12 in C. elegans and FXR in humans.  

This suggests a link to the gut-brain connection, he explains. A reduction in the level of the hormone receptor impedes the expression of TFEB and the liposomal genes required for clearing up damaged mitochondria. 

DAF-12/FXR is extremely important for liposome metabolism where bile acids are known to play several roles, continues Chamoli. They are also regulated by the microbiome, home to bacterial metabolites that can transform primary bile acids into secondary bile acids that act as receptors for FXR and thus regulate its activity and mitophagy. 

Changes in the microbiome occur with aging as well as many disease conditions. If that means a loss of certain kinds of bacteria required to form these bile acids, then the mitochondria clearing process inside nerve cells in the brain will be impaired. 

In essence, MIC is being used to bypass the ligand that might be naturally produced by the microbiome to prompt production of bile acids important to tissue and neuronal health, says Lithgow. 

When the project started, Andersen adds, precious little information existed about how TFEB was transcriptionally regulated. She found only one published paper about the abilities of the hormone receptor within human cells, and a couple about the regulation of mitophagy through TFEB during feed/fast cycles. 

It was quite surprising to see the effects of DAF-12/FXR in the brain, but only because no one had thought to look before, she says. Since mitophagy pathways exist throughout the body, the finding has implications for many different tissues and disease states. 

Compound Shortage

The Buck research team is currently conducting a NIH-funded study looking at the impact of MIC in a preclinical Alzheimer’s disease model where neuropathology is being assessed based on cognitive assays in mice, says Andersen. She, Lithgow, and Chamoli are cofounders of Symbiont Bio, a spin-out from the Buck Institute for Research on Aging that will be endeavoring to bring therapeutics for aging and age-related diseases to market. 

Symbiont will be adopting Buck’s geroscience approach to drug development by going after the fundamental hallmarks of aging, like mitochondrial dysfunction, that are likely to also have an impact on all the aging-related diseases, says Chamoli. 

“In the medical community, a very small fraction of people is buying into this idea that normal aging causes disease,” adds Lithgow. Treating or preventing chronic diseases of life by targeting aging addresses two unmet needs—drugs for debilitating conditions like Alzheimer’s and Parkinson’s and drugs that can slow aging, especially in mammals. 

Beyond rapamycin and metformin, the two “potentially outstanding candidates for clinical trials right now,” and a handful of metabolites not yet ready for testing in humans, the number of compounds under study is miniscule, Lithgow says. “We need hundreds of compounds if this field is really going to take off.” 

As Andersen so aptly points out, “No one wants to get Alzheimer’s at 75 and then live to be 100.”