Tricking Time in a Disease of Aging

Descriptions of major disorders like cancer, lung disease and heart disease date to at least 1500 B.C.—but ALS wasn’t identified until 1869, and it wasn’t widely known until 1939, when baseball player Lou Gehrig was diagnosed.

Because ALS typically presents between the ages of 55 and 75, perhaps a shift in life expectancy—from under 40 in premodern times to a turn-of-the-20th-century increase— could explain why the neurodegenerative disease was undocumented before the modern era. But if ALS is a consequence of our expanded longevity, what explains why it strikes in old age? What are the hazards in aging?

After discovering, as outlined in a 2016 Nature Neuroscience study, that motor neurons derived from iPSCs of ALS patients more closely resemble fetal cells than adult cells, Ritchie Ho, PhD, is attempting to “age” them in the lab to more faithfully model late-onset disease. He hopes to accelerate iPSC maturation—to synthesize a lifespan—and search for signs of preprogrammed cellular “events” that instigate the onset of ALS.

“If we can activate the aging program, we can start to see the neurons become diseased and die, and how,” Dr. Ho says. “We’re trying to look at the very early origins of ALS, assuming there’s something in the neuron that sets it up to die, and trying to understand what that is in order to intervene before it manifests in paralysis.”

To try to trick time, Dr. Ho is measuring gene expressions of iPSC-built motor neurons against gene expressions in tissue from ALS patients and healthy patients. He’s attempting to adjust the manufactured cells to better mimic adult cells by adding small molecules known to switch genes on and off.

In theory, the artificial, expedited aging of iPSCs can help identify what triggers disease onset, Dr. Ho says. “If we can see the full cycle of ALS from start to finish—how the cellularenergy expenditure is different, how proteins accumulate and, at the last stage, how cells are dying—we can pick it apart and see where along a lifespan the disease processes happen.” offers hope. Scientists at Houston Methodist are focused on immunotherapy: A 2022 study published in Neurology proved the safety of the intravenous application of T-cells meant to slow ALS progression. Another trial, completed at six sites including Cedars-Sinai, met safety benchmarks for the infusion of ALS patients’ own bone marrow stem cells into their spinal fluid; but a Phase III study, published in a

2022 Muscle Nerve paper, did not meet its efficacy endpoint.

Dr. Lewis remains focused on stem cells’ potential for progress and hopes that continued clinical trials will validate the approach.

“We are not going to be able to convert this into a therapy for people who currently have the disease,” he says. “But the scientific question is an important one, and the fact that the stem cells survive is crucial—it’s a start.”