The short answer: CNS regeneration is a completely different problem. Schwann cell senescence explains why aging peripheral nerves heal poorly, but CNS axons fail to regenerate for reasons that go far beyond glial support cells.

In the periphery, axons retain intrinsic growth capacity. The problem is the environment—senescent Schwann cells stop producing the growth factors and guidance cues needed. Clear them or restore c-Jun, and axons grow again.

CNS axons are different. Even when placed in a permissive peripheral nerve graft, most CNS neurons show minimal regeneration. The issue is cell-intrinsic: developmental downregulation of growth-related genes, including those for cytoskeletal remodeling and axon guidance.

That said, there is some interesting work on glial senescence in the CNS. Oligodendrocyte precursor cells (OPCs) show age-related changes that impair remyelination. Astrocyte reactivity increases with age. But unlike Schwann cells, these are not the primary bottleneck for CNS axon regeneration.

For translation to humans, the peripheral nerve work is actually more promising precisely because the problem is simpler. CNS interventions will likely need to both unlock intrinsic growth programs AND modify the environment. The peripheral work shows that fixing the environment alone can work when axons are ready to grow.

Species differences exist but are not the main concern. Mouse and human Schwann cells behave similarly. The bigger question is whether senolytic dosing in humans can achieve the same clearance rates seen in mice without unacceptable side effects.

The CNS question is important because Schwann cells are PNS-specific. In the CNS, oligodendrocytes handle myelination—and they behave very differently after injury.

Oligodendrocytes do not transform into repair cells the way Schwann cells do. They tend to undergo apoptosis or become dysfunctional rather than activating regenerative programs. The c-Jun pathway I described does not apply directly.

That said, senescence mechanisms might still matter. Astrocytes in the CNS do become senescent after injury, and they secrete similar SASP factors that inhibit regeneration. But the therapeutic approach would differ—targeting astrocyte senescence rather than Schwann cell senescence.

On human translation: we are still early. The Pain et al. study I cited was in mice. No human trials specifically targeting Schwann cell senescence for peripheral nerve injury are recruiting yet. The closest is broader senolytic trials for age-related conditions—UNITY Biotechnology has tested UBX1325 in diabetic macular edema, which showed some efficacy.

Species differences are a real concern. Mouse peripheral nerves regenerate much better than human nerves even in young animals. The baseline regenerative capacity differs, so the relative benefit of clearing senescent cells might be smaller in humans.

I think the first human application will be in diabetic neuropathy or chemotherapy-induced peripheral neuropathy, where the patient population is larger and the endpoint (pain reduction, not regeneration) is easier to measure.

The short answer: CNS regeneration is a completely different problem. Schwann cell senescence explains why aging peripheral nerves heal poorly, but CNS axons fail to regenerate for reasons that go far beyond glial support cells.

In the periphery, axons retain intrinsic growth capacity. The problem is the environment—senescent Schwann cells stop producing the growth factors and guidance cues needed. Clear them or restore c-Jun, and axons grow again.

CNS axons are different. Even when placed in a permissive peripheral nerve graft, most CNS neurons show minimal regeneration. The issue is cell-intrinsic: developmental downregulation of growth-related genes, including those for cytoskeletal remodeling and axon guidance.

That said, there is some interesting work on glial senescence in the CNS. Oligodendrocyte precursor cells (OPCs) show age-related changes that impair remyelination. Astrocyte reactivity increases with age. But unlike Schwann cells, these are not the primary bottleneck for CNS axon regeneration.

For translation to humans, the peripheral nerve work is actually more promising precisely because the problem is simpler. CNS interventions will likely need to both unlock intrinsic growth programs AND modify the environment. The peripheral work shows that fixing the environment alone can work when axons are ready to grow.

Species differences exist but are not the main concern. Mouse and human Schwann cells behave similarly. The bigger question is whether senolytic dosing in humans can achieve the same clearance rates seen in mice without unacceptable side effects.

You are right to worry about this. Systemic senolytics like navitoclax or the dasatinib+quercetin combo clear cells across tissues, and we do not fully understand the tradeoffs.

Here is the thing: in Pain et al.'s study, the D+Q cocktail was delivered systemically, and peripheral nerves responded strongly. Schwann cells appear to be effectively exposed whether you go local or systemic.

But your point about off-target effects stands. Senescent cells are not purely harmful—they have roles in wound healing and development. Clearing them everywhere could backfire.

Some alternatives are being explored:

Targeted approaches that hit specific SASP factors or p16INK4a-high cells only in nerve tissue. Local delivery via intrathecal or perineural injection could achieve high concentrations at the injury site without systemic exposure. There is also work on hydrogel depots that release senolytics slowly right where they are needed.

Another angle: intermittent dosing. Mayo Clinic trials suggest monthly pulses may clear accumulated senescent cells without the risks of continuous suppression.

You are correct that systemic clearance is a blunt instrument. For peripheral nerve injuries in older adults, local or targeted approaches would be preferable. The complication is that Schwann cell senescence in aging is diffuse throughout the nerve—not just at injury sites—so truly localized treatment might miss cells that later impair regeneration.

The mouse studies used systemic delivery because it is experimentally simpler. Human trials will need smarter targeting, and that work is still ongoing.

You are right to worry about this. Systemic senolytics like navitoclax or the dasatinib+quercetin combo clear cells across tissues, and we do not fully understand the tradeoffs.

Here is the thing: in Pain et al.'s study, the D+Q cocktail was delivered systemically, and peripheral nerves responded strongly. Schwann cells appear to be effectively exposed whether you go local or systemic.

But your point about off-target effects stands. Senescent cells are not purely harmful—they have roles in wound healing and development. Clearing them everywhere could backfire.

Some alternatives are being explored:

Targeted approaches that hit specific SASP factors or p16INK4a-high cells only in nerve tissue. Local delivery via intrathecal or perineural injection could achieve high concentrations at the injury site without systemic exposure. There is also work on hydrogel depots that release senolytics slowly right where they are needed.

Another angle: intermittent dosing. Mayo Clinic trials suggest monthly pulses may clear accumulated senescent cells without the risks of continuous suppression.

You are correct that systemic clearance is a blunt instrument. For peripheral nerve injuries in older adults, local or targeted approaches would be preferable. The complication is that Schwann cell senescence in aging is diffuse throughout the nerve—not just at injury sites—so truly localized treatment might miss cells that later impair regeneration.

The mouse studies used systemic delivery because it is experimentally simpler. Human trials will need smarter targeting, and that work is still ongoing.

You are asking exactly the right question. Both approaches work in mice, but they solve slightly different problems.

Senolytics clear the problematic cells entirely. This removes the SASP inflammatory soup and lets fresh Schwann cells take over. Pain et al. showed this rescues regeneration to youthful levels. The downside: you lose the cellular infrastructure. Schwann cells do not just guide axons—they form the bands of Bünger that act as highways for regeneration. Clear too many and you might create gaps.

c-Jun restoration keeps the cells but changes their behavior. Arthur-Farraj's team showed genetic c-Jun overexpression makes aged Schwann cells function like young ones again. The cells stay in place, maintain the repair scaffold, but switch from senescent to regenerative mode. The catch: delivering transcription factors is harder than clearing cells. You need gene therapy or small molecules that activate c-Jun specifically in Schwann cells without off-target effects.

Head-to-head comparisons are sparse. Most studies test one approach or the other, not both in the same model. Theoretically, c-Jun restoration might be better for diffuse age-related decline where you need all the Schwann cells you can get. Senolytics might work better for focal injuries where you can afford to lose some cells locally.

I lean toward c-Jun restoration for clinical translation, but only because delivery methods are advancing faster. Senolytics are already in human trials for other conditions, so they might reach nerve patients sooner even if they are not the optimal long-term solution.

What do you think—would you take the risk of cell loss for a faster path to clinic?

You are asking exactly the right question. Both approaches work in mice, but they solve slightly different problems.

Senolytics clear the problematic cells entirely. This removes the SASP inflammatory soup and lets fresh Schwann cells take over. Pain et al. showed this rescues regeneration to youthful levels. The downside: you lose the cellular infrastructure. Schwann cells do not just guide axons—they form the bands of Bünger that act as highways for regeneration. Clear too many and you might create gaps.

c-Jun restoration keeps the cells but changes their behavior. Arthur-Farraj's team showed genetic c-Jun overexpression makes aged Schwann cells function like young ones again. The cells stay in place, maintain the repair scaffold, but switch from senescent to regenerative mode. The catch: delivering transcription factors is harder than clearing cells. You need gene therapy or small molecules that activate c-Jun specifically in Schwann cells without off-target effects.

Head-to-head comparisons are sparse. Most studies test one approach or the other, not both in the same model. Theoretically, c-Jun restoration might be better for diffuse age-related decline where you need all the Schwann cells you can get. Senolytics might work better for focal injuries where you can afford to lose some cells locally.

I lean toward c-Jun restoration for clinical translation, but only because delivery methods are advancing faster. Senolytics are already in human trials for other conditions, so they might reach nerve patients sooner even if they are not the optimal long-term solution.

What do you think—would you take the risk of cell loss for a faster path to clinic?

You are asking exactly the right question. Both approaches work in mice, but they solve slightly different problems.

Senolytics clear the problematic cells entirely. This removes the SASP inflammatory soup and lets fresh Schwann cells take over. Pain et al. showed this rescues regeneration to youthful levels. The downside: you lose the cellular infrastructure. Schwann cells do not just guide axons—they form the bands of Bünger that act as highways for regeneration. Clear too many and you might create gaps.

c-Jun restoration keeps the cells but changes their behavior. Arthur-Farraj's team showed genetic c-Jun overexpression makes aged Schwann cells function like young ones again. The cells stay in place, maintain the repair scaffold, but switch from senescent to regenerative mode. The catch: delivering transcription factors is harder than clearing cells. You need gene therapy or small molecules that activate c-Jun specifically in Schwann cells without off-target effects.

Head-to-head comparisons are sparse. Most studies test one approach or the other, not both in the same model. Theoretically, c-Jun restoration might be better for diffuse age-related decline where you need all the Schwann cells you can get. Senolytics might work better for focal injuries where you can afford to lose some cells locally.

I lean toward c-Jun restoration for clinical translation, but only because delivery methods are advancing faster. Senolytics are already in human trials for other conditions, so they might reach nerve patients sooner even if they are not the optimal long-term solution.

What do you think—would you take the risk of cell loss for a faster path to clinic?

The c-Jun/IIS connection is something I have been thinking about. AP-1 factors including c-Jun do interact with FOXO pathways, and both are regulated by mTOR. The interesting question is whether Schwann cell senescence represents a developmental program being misactivated rather than a tumor-suppression mechanism running off the rails.

Your point about naked mole-rats is relevant here. They maintain regenerative capacity throughout life—older NMRs heal peripheral nerve injuries as well as young ones. If they suppress senescence entry rather than just clearing senescent cells, the mechanism might be upstream of c-Jun in the signaling cascade.

One possibility: IIS/mTOR signaling in NMRs is tuned for maintenance over growth. Lower baseline mTOR activity would reduce senescence pressure and keep repair programs accessible. This is speculation, but Pain et al.'s finding that c-Jun suppression correlates with senescence suggests the pathway is regulated by nutrient sensing.

The evolutionary angle you raise is interesting. Schwann cells do proliferate during development and after injury—Wallerian degeneration triggers massive Schwann cell division. So the senescence machinery makes sense as cancer protection. But in aging, it gets overactivated. Perhaps the threshold for senescence entry drops as repair programs become harder to activate.

I have not seen direct data on c-Jun and IIS/mTOR in Schwann cells specifically. Most of that work is in neurons or proliferating cell lines. This might be a gap worth filling—understanding how metabolic signals regulate the repair-to-senescence transition could give us better therapeutic targets than either clearing cells or forcing transcription factors.

The evolutionary comparison to naked mole-rats is spot on. NMRs maintain regenerative capacity throughout their 30+ year lifespan, suggesting they have solved the senescence problem differently—not by clearing cells more efficiently, but by preventing the repair-to-senescence transition in the first place.

Your c-Jun/IIS hypothesis makes mechanistic sense. c-Jun is downstream of JNK, which sits at the crossroads of stress signaling and metabolic regulation. In standard aging, chronic mTOR activation shifts cells toward anabolism and away from maintenance. Schwann cells under metabolic stress might default to senescence rather than repair.

One testable prediction: NMR-derived Schwann cells should show sustained c-Jun expression after injury even in old age. If their IIS/mTOR signaling is tuned for maintenance, the threshold for repair activation would stay low throughout life.

The comparison to negligibly senescent species raises a broader question. Is Schwann cell senescence in mammals an adaptive tradeoff—accepting regenerative decline in exchange for tumor suppression—or simply a failure mode that evolution never optimized because peripheral nerve injuries were rarely survived in the wild?

I suspect the latter. Most animals that suffered severe nerve injuries in nature died before reproducing, so there was little selection pressure to maintain repair capacity into old age. The naked mole-rat lives its entire life in a protected underground colony where even injured individuals might survive and reproduce. This could have driven selection for sustained repair capacity.

Have you looked at whether other subterranean mammals show similar sustained regeneration? If the protected-environment hypothesis is right, Damaraland mole-rats and other bathyergids might share this trait.

The c-Jun/IIS connection is something I have been thinking about. AP-1 factors including c-Jun do interact with FOXO pathways, and both are regulated by mTOR. The interesting question is whether Schwann cell senescence represents a developmental program being misactivated rather than a tumor-suppression mechanism running off the rails.

Your point about naked mole-rats is relevant here. They maintain regenerative capacity throughout life—older NMRs heal peripheral nerve injuries as well as young ones. If they suppress senescence entry rather than just clearing senescent cells, the mechanism might be upstream of c-Jun in the signaling cascade.

One possibility: IIS/mTOR signaling in NMRs is tuned for maintenance over growth. Lower baseline mTOR activity would reduce senescence pressure and keep repair programs accessible. This is speculation, but Pain et al.'s finding that c-Jun suppression correlates with senescence suggests the pathway is regulated by nutrient sensing.

The evolutionary angle you raise is interesting. Schwann cells do proliferate during development and after injury—Wallerian degeneration triggers massive Schwann cell division. So the senescence machinery makes sense as cancer protection. But in aging, it gets overactivated. Perhaps the threshold for senescence entry drops as repair programs become harder to activate.

I have not seen direct data on c-Jun and IIS/mTOR in Schwann cells specifically. Most of that work is in neurons or proliferating cell lines. This might be a gap worth filling—understanding how metabolic signals regulate the repair-to-senescence transition could give us better therapeutic targets than either clearing cells or forcing transcription factors.

The c-Jun/IIS connection is real, and the research on this is more specific than I initially thought. c-Jun and mTORC1 rise together after injury—mTORC1 activation is actually necessary for full c-Jun upregulation. When researchers delete Raptor (blocking mTORC1) in Schwann cells, c-Jun fails to activate properly and dedifferentiation stalls.

Your point about naked mole-rats is spot on. They maintain regenerative capacity throughout their 30+ year lifespan, suggesting they have solved the senescence problem differently—not by clearing cells more efficiently, but by preventing the repair-to-senescence transition in the first place.

The evolutionary angle you raise is interesting. Schwann cells do proliferate during development and after injury—Wallerian degeneration triggers massive Schwann cell division. So the senescence machinery makes sense as cancer protection. But in aging, it gets overactivated. Perhaps the threshold for senescence entry drops as repair programs become harder to activate.

One testable prediction: NMR-derived Schwann cells should show sustained c-Jun expression after injury even in old age. If their IIS/mTOR signaling is tuned for maintenance, the threshold for repair activation would stay low throughout life.

The complication is that persistent mTORC1/c-Jun elevation without resolution can actually lock cells in a dysfunctional pro-repair state. Metabolic stress that keeps both pathways active chronically leads to pathology. So it is not just about keeping c-Jun high—it is about the dynamics of when it rises and falls.

I have not seen direct data on c-Jun and IIS/mTOR in Schwann cells specifically. Most of that work is in neurons or proliferating cell lines. This might be a gap worth filling—understanding how metabolic signals regulate the repair-to-senescence transition could give us better therapeutic targets than either clearing cells or forcing transcription factors.

Have you looked at whether other subterranean mammals show similar sustained regeneration? If the protected-environment hypothesis is right, Damaraland mole-rats and other bathyergids might share this trait.