Pictured: an abstract of a woman’s face/agsandrew, iStock
The quest for the fountain of youth—longevity—has inspired the launch of several biotech startups over the past five years, including Rejuvenate Bio and Altos Labs. It was also a hot topic at the Biomed Israel conference last week, where a panel zeroed in on how to not only extend human lives but healthy human lives—the so-called healthspan.
“Longevity is a big word,” said panelist Silvia Noiman, founder, chair and CEO of IMEL Biotherapeutics, a company targeting diseases of aging at the mitochondrial level with cell therapy. It covers a broad space composed of companies focused on everything from the genome and epigenome to mitochondria and cellular senescence.
Progress has already been made, said Nir Barzilai, panelist and director of the Einstein Institute for Aging Research and professor of medicine and genetics at Albert Einstein College of Medicine.
“Life expectancy of humans was 20 or 30 years through a hundred thousand years of evolution,” he told BioSpace. “In the last 150 years, we’ve tripled life expectancy.”
But there is still untapped potential, he said. Based on statistical modeling, the current maximum human lifespan is 115 years, he explained—nearly four decades longer than the average life expectancy in the U.S. as of 2021, according to the CDC.
“Passing the age of 60, we started getting diseases that were never part of human evolution,” he said. “People didn’t die from Alzheimer’s, from cardiovascular disease, from cancers.”
However, Barzilai said that 30% of the centenarians he sees in his practice do not have any disease, suggesting that humans have more healthspan to be realized. He and his colleagues are working to extend this genetic advantage to everyone else through drug development.
Of the 50 drugs approved by the FDA in 2021, two-thirds were based on genetic findings, according to a study published in Nature.
“If you have a genetic finding, you usually can develop a drug that will do what these mutations or changes in the DNA have done,” Barzilai said. “The obvious thing is to develop a drug that will behave like the genetic problem, or in our case, the genetic advantage.”
Regulating Gene Expression
Rejuvenate Bio is doing just that. The biotech, spun out of George Church’s lab at Harvard Medical School, is targeting what it calls the core drivers of age-related disease with gene expression and epigenetic reprogramming.
Rejuvenate views aging as a change in gene expression, Daniel Oliver, co-founder and CEO, told BioSpace. “What causes you to have a dysregulated system or a malfunctioning system, really comes down to what set of genes are being turned on and off at what time.” Past the typical age of procreation, “there really isn’t a strong evolutionary mechanism to keep those gene expression profiles constant, so they tend to dysregulate,” he said.
The company’s lead program, RJB-01, is an adeno-associated virus (AAV)–based gene therapy that delivers two genes—FGF21 and TGF-β1—associated with overall lifespan in transgenic mouse models. When FGF21 was upregulated in every cell in a mouse’s body, the animal’s lifespan increased by about 30%, Oliver said. Conversely, downregulating TGF-β1 led to a lifespan increase of about 15%.
FGF21 metabolizes fat during periods of fasting, increases insulin sensitivity and reactivates the immune system, according to Rejuvenate. Preclinical studies show that targeting FGF21 is effective for weight loss and diabetes in mice. TGF-β1 activation, meanwhile, is a driver of fibrosis and numerous cancers, and previous clinical trials have shown that its inhibition prevented tumor growth in patients with previously treated colorectal cancer.
TGF-β1expression increases with age, while FGF21 levels peak in one’s 20s and 30s and continuously drop with age, Oliver said. “Our goal is to re-regulate those gene expression profiles to what they were when our patients were younger, but more importantly, healthier.”
Rejuvenate plans to submit an IND in 2024 to study RJB-01 in a genetic subpopulation of arrhythmogenic cardiomyopathy patients, he said. While such patients are rare, he said the gene therapy could eventually treat other forms of cardiomyopathy as well.
The company’s second technology, also still in the preclinical stage, seeks to extend human lifespan with epigenetic reprogramming. Rejuvenate has created a gene therapy that delivers a set of transcription factors and controls their expression. In a mouse study, published in January as a preprint on the bioRxiv server, Rejuvenate showed that gene therapy could double the remaining lifespan of 124-week-old mice and reverse age-related changes.
Reenergizing the Cell
At IMEL Biotherapeutics, researchers aim to increase longevity with cell therapy. Specifically, they have their sights set on the mitochondrion, the organelle that generates energy for nearly every organ in the body.
“[It] is key both for the energy of the youth and for the deterioration of the aged,” IMEL’s Noiman told BioSpace. “If you can give a little bit of this energy to the aged population . . . in theory, you can actually affect all of the systems in the body.”
IMEL intends to do this by replacing dysfunctional mitochondria and increasing the number of healthy organelles in a cell with its MirC process.
IMEL’s lead program targets immunosenescence, the exhaustion of the immune system. Noiman noted the immune system’s involvement in cancer, cardiovascular disease, Alzheimer’s and Parkinson’s.
“Mitochondria [have] a major role in the development of the T cells, and when [they are] not working properly, the development of the T cells will not work properly,” Noiman said. “The improvement of T cell activation will have a major effect on the activity of T cells in cancer,” she continued, noting that the effect could be particularly felt in CAR T and tumor-infiltrating lymphocytes (TIL) therapies.
If preclinical studies are successful, Noiman said IMEL plans to launch a Phase I clinical trial in solid tumors.
A Lucrative Space
A total $5.2 billion poured into the longevity space in 2022 through 130 deals, according to Longevity.Technology. Among the largest was the $3 billion in financing raised by Altos Labs in January 2022.
“I think the interesting thing about longevity today is that the molecular science really has caught up,” Jens Eckstein, Biomed Israel panelist and partner at Apollo Health Ventures, told BioSpace. “The time is now ripe for targets that will actually have an impact on healthspan.” Eckstein highlighted the mechanistic target of rapamycin (mTOR) pathway, a master regulator of cell growth and division. Of all drugs, he said, rapamycin has had the largest effect on healthspan and longevity in animal trials.
For Eckstein, the potential for longevity comes down to the individual. In terms of therapeutic interventions, “it’s going to be ultra-personalized,” he said, as only 20% is determined by genetics. The rest, he said, comes down to epigenetics and other factors such as diet and zip code.
Eckstein said he believes the first medicines to treat age-related disease will be on the market in 10 years. Even more than that, though, he said he is excited about the potential of longitudinal datasets that will enable middle-aged people to get baseline omics assessments to help inform which therapies will work best for them. “Once we do that, that’s the real game changer.”
Heather McKenzie is a senior editor at BioSpace, focusing on neuroscience, oncology and gene therapy. You can reach her at firstname.lastname@example.org. Follow her on LinkedIn and Twitter: @chicat08
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