To Reverse Aging’s Clock, Adjust the Cell’s Machinery

If we want to increase longevity and reverse aging, we need to get serious. Forget myth. There is no fountain of youth. And we need to move beyond practical advice. Healthy habits will accomplish only so much. No, if we want to make real progress, we need to act on what we’ve been learning about cell biology.

This idea isn’t all that new. Almost 10 years ago, a review in the Molecular Biology of the Cell (2015; 26: 4524–4531) noted that cell biology research has been finding all sorts of processes behind aging: “[Cellular] health in aging … is controlled at various points in the cell, starting in the nucleus through chromosome structure/organization, transcriptional regulation, and nuclear export/import, ranging outward to protein translation and quality control, autophagic recycling of organelles, maintenance of cytoskeletal structure, and finally maintenance of the extracellular matrix and extracellular signaling. Each regulatory system receives information from every other system, resulting in an intricate interplay of regulation controlling the aging of the cell.”

Needless to say, such points of control are also potentially points of intervention, that is, points at which new therapies may preserve or restore cellular health, and thereby forestall or even reverse aging. Several new therapies of this type are in development. Some of them have already advanced to clinical trials.

In this article, we will be looking at four new therapeutic approaches. The first is a gene expression rheostat that involves an engineered inducible adeno-associated virus type 2 (AAV2) vector that contains three specific transcription factors and is capable of up- or downregulating the expression of targeted genes. The second is based on an atlas of the body’s electrome, a map of nonneural communications for modulating ion channels as conduits for bioelectric signaling. The third is a synaptic regenerative approach based on small-molecule drugs. And, finally, the fourth is a new senolytic approach, that is, an approach for modulating or reversing cellular senescence.

Epigenetic reprogramming

“There’s a whole host of hallmarks of aging—it’s not just ‘wear and tear,’” declares Sharon Rosenzweig-Lipson, PhD, chief scientific officer, Life Biosciences. “There are biological processes underlying aging, one of which is a change in the epigenome. The epigenome is affected by many things that change methylation status without altering DNA. By using epigenetics to modify DNA methylation profiles, we can change gene expression.”

Life Biosciences is targeting cellular rejuvenation and age-related diseases by focusing on partial epigenetic reprogramming as well as chaperone-mediated autophagy strategies. The company’s epigenetics platform is based on research that won half the 2012 Nobel Prize in Physiology or Medicine. This research, which was conducted by Shinya Yamanaka, MD, PhD, when he was affiliated with Kyoto University and the Gladstone Institutes, identified four factors (now called the “Yamanaka factors”) that can reprogram mature cells to become pluripotent.

The company is also building on the work of David A. Sinclair, PhD, a researcher at Harvard University who, Rosenzweig-Lipson notes, determined that we need “only three of the four factors to take mature, injured, or aged cells and dial them back to a more youthful version of themselves.” These three factors are OCT4, SOX2, and KLF4, which are collectively known as OSK.

Life Biosciences has used its platform to produce a gene therapy candidate called ER-100 that uses an AAV2 vector and enables ectopic expression of the OSK factors. ER-100 has been preclinically tested as an intravitreal injection in optic neuropathies such as glaucoma and nonarteritic anterior ischemic optic neuropathy.

“In gene therapy, the gene is changed forever,” Rosenzweig-Lipson points out. “In our case, we are not changing any genes, we are expressing three inducible transcription factors, and in doing so, we can turn genes off and on to change their levels of expression. ER-100 is the complex of vectors used at Harvard early on in eye and retina. It showed efficacy in a host of different models of glaucoma. We’ve taken that to the next step and tested it in nonhuman primates for ocular disease. We expect to take this to clinical trials next year.”

The company is also targeting chaperone-mediated autophagy, a biological process that normally removes unwanted or degraded proteins from cells, but which declines with aging. Rosenzweig-Lipson discloses, “We have a chaperone-mediated autophagy medicinal chemistry discovery program to treat neurological diseases, such as Alzheimer’s disease and Parkinson’s disease, and ocular disorders.”

“We are seeing a transformative shift in how we understand the biology of aging,” Rosenzweig-Lipson relates. “It is changing how we address the interplay of biological mechanisms driving the aging process.”

Mapping the bioelectrome

Just when you think you know all the “omes,” another emerges. One of the newly recognized omes is the bioelectrome, and it could prove to be key to the induction of regeneration and the treatment of diseases, including diseases of aging. “The bioelectrome is the set of communication networks within the body that binds multicellular collectives together for a common purpose, maintaining tissue- and organ-level integrity and health,” says Jim Jenson, PhD, CEO of the startup Morphoceuticals. “It is ancient and highly conserved, yet largely untapped for therapeutic uses.”

Jenson says that the bioelectrome allows a form of nonneural cognition in which ion channels are modulated to channel bioelectric signals. He adds that “by understanding and manipulating these bioelectric patterns, we can potentially rewrite them for the treatment of many conditions that are currently inadequately addressed by other modalities.” The conditions that could be treated include degenerative diseases, organ failure, and traumatic injuries.

Progress toward bioelectrome-based treatments requires vast amounts of data about bioelectric signaling. For example, such data could reveal differences between tissue types and between normal and disease states.

To contribute to such work, Morphoceuticals is building a bioelectrome atlas. “We’re using our world-first suite of model systems and proprietary artificial intelligence techniques,” Jenson asserts. “Development of the atlas requires us to employ the tools of multiomics, electrophysiology, and machine learning to generate a voltage atlas of the body and a map of its druggable components.”

Jenson adds that the company’s scientific co-founders have made significant advances with their research that could be translated to achieve “real impact for patients in need.” The co-founders are Michael Levin, PhD, Vannevar Bush Professor of Biology in the School of Arts and Sciences, and David Kaplan, PhD, Stern Family Endowed Professor of Engineering in the School of Engineering, both of Tufts University.

Jenson says that after the foundation of the atlas has been built, the company will start using it to support the development of regenerative medicines. “Like any early-stage company, we are in pursuit of collaborations with investors and strategic partners,” he relates. “We’re currently well financed to meet our upcoming objectives. We expect numerous papers validating our approach to be published in the months ahead.”

Jenson believes that Morphoceuticals’ work is groundbreaking. He suggests that the creation of a bioelectrome atlas will not only help the company advance its own therapeutic candidates, but also “open a new field of bioelectromics on which other companies will build.”

Regenerating synapses

In normal aging, cognitive function and memory dwindle. “A wealth of data indicates that this age-related functional decline is due in large part to changes in synaptic connectivity and function, rather than neuron loss,” explains Peter Vanderklish, PhD, chief scientific officer, Spinogenix. “We also know that loss of synapses is a common early pathology across age-related neurodegenerative conditions like amyotrophic lateral sclerosis and Alzheimer’s disease, indicating synapse loss and dysfunction could in fact be a driver of early pathology and symptom onset in these conditions, not just a consequence of disease progression.”

Currently, there are no approved therapeutics that regenerate synapses to reverse the course of these and other such diseases. Why? According to Vanderklish, “Perhaps the biggest reason it has been so difficult to develop such therapies stems from the complexities of synaptic function and the intricate molecular processes that underlie it. Glutamatergic synapses in particular can be viewed as one of the most complex subcellular specializations in the entire body.”

To grapple with these complexities, the company is developing first-in-class synaptic-regenerative small molecules that effectively penetrate the blood-brain barrier and that can regenerate glutamatergic synapses to partially restore function.

“Our lead candidate for neurodegenerative and neuropsychiatric disorders, SPG302, has been developed with our TAGS technology,” Vanderklish elaborates. “TAGS stands for Transient Activators of Glutamatergic Synaptogenesis, and TAGS drugs have a unique set of properties. For example, as a TAGS drug, SPG302 has the remarkable ability to trigger the formation of new synapses that use the amino acid glutamate as a neurotransmitter.”

In preclinical studies, SPG302 was shown to improve cognition and motor behaviors in multiple animal models of neurodegenerative disorders, including a model of cervical spinal cord injury, where SPG302 greatly improved the recovery of respiratory function. “Across several in vivo model systems, we see synaptic and behavioral benefits within weeks of daily treatment,” Vanderklish says, “and there’s evidence that these effects are durable, leading to retention of new synapses for weeks or more.”

SPG302 is currently in Phase II studies in both amyotrophic lateral sclerosis and Alzheimer’s disease. These are not the only indications that are in Spinogenix’s sights. “We believe that a synaptic regenerative approach has the potential to benefit people with a variety of synaptopathies,” Vanderklish declares. “This approach could be used to treat neurodegenerative diseases, neuropsychiatric conditions, and neurodevelopmental disorders, including movement disorders as well as injury and aging.”

Targeting senescent cells

When cells enter a state of senescence, they remain metabolically active, yet they also secrete various inflammatory factors and harmful proteins. “These secretions damage nearby healthy tissues, leading to cellular dysfunction and tissue degeneration,” observes Anirvan Ghosh, PhD, CEO, Unity Biotechnology. “As we age and these senescent cells accumulate, they contribute to several diseases that take a tremendous toll on our health and quality of life—including diabetic macular edema.”

Unity develops senolytics, which selectively eliminate or modulate senescent cells, and it has a focus on retinal diseases. “We are developing a small molecule that inhibits Bcl-xL, a member of the Bcl-2 family of apoptosis regulatory proteins that is highly expressed in pathological blood vessels in the retina,” Ghosh elaborates. “Senescent cells have been shown to rely on Bcl-xL for survival.

“By targeting Bcl-xL, we can eliminate senescent cells and thereby stymie the production of vascular endothelial growth factor at the source in diabetic retinas. When new blood vessels form, these bring more oxygen and metabolic support back to the retina, potentially improving retinal function and reducing vascular leakage.”

The company’s lead candidate, UBX1325, is a potent Bcl-xL inhibitor that has been demonstrated to selectively target and eliminate senescent cells in vitro and to inhibit retinal neovascularization, reduce vascular leakage, and improve retinal function in preclinical disease models. “UBX1325 has been evaluated in Phase I and Phase II studies, which have shown that it is safe and well tolerated to date with a strong efficacy signal,” Ghosh says. “We’re currently enrolling patients with diabetic macular edema for a Phase IIb study (ASPIRE), which will evaluate UBX1325 head-to-head against the current standard-of-care treatment.”

Unity also has additional candidates in its antiaging pipeline. “We are exploring other pathways of aging that may be relevant to disease progression,” Ghosh points out. “These include the Tie2 pathway for retinal diseases and the alpha-Klotho pathway for cognitive decline. Both the Tie2 and Klotho programs use biologics as a modality.”

Ghosh believes that focusing on modulating or reversing cellular senescence could have an impact on many chronic and inflammatory diseases: “Senolytics can provide long-lasting, disease-modifying benefits to patients that have diseases that are taking a tremendous toll on their health and independence as they age.”

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