Shernan Holtan: Does Sirolimus Slow the Clock After Allogeneic HCT? (hematopoietic cell transplant)

#1

This is a common question people have had about rapamycin; in the traditional clinical applications that rapamycin is used in, are the patients showing any “anti-aging” effects or benefits… and this time the issue is brought up by a researcher at Roswell Park, where Blagosklonny used to work.

Shernan Holtan, Chief of Blood and Marrow Transplantation and Professor of Medicine at Roswell Park Comprehensive Cancer Center, shared a post on LinkedIn:

“Conflict of research interest: I prescribe sirolimus and also feel myself rapidly aging, so naturally I’ve always wondered if sirolimus helped slow the clock when used in allogeneic HCT. Hats off to Najla El Jurdi and Matt Yousefzadeh for digging into this question!

In this unique pilot analysis, standard sirolimus dosing didn’t meaningfully lower senescence markers compared with cyclosporine. Maybe the senotherapeutic window is narrower than how we use it in BMT, and we still need to look for better ways to address age acceleration after cancer therapy.”

source: Shernan Holtan: Does Sirolimus Slow the Clock After Allogeneic HCT? - OncoDaily

Open access paper: Frontiers | Sirolimus use in allogeneic hematopoietic cell transplant recipients: assessing its senotherapeutic role in a high risk population

Sirolimus use in allogeneic hematopoietic cell transplant recipients: assessing its senotherapeutic role in a high risk population

AI Summary of Paper:

Here’s a summary and a discussion of what seems novel in “Sirolimus use in allogeneic hematopoietic cell transplant recipients: assessing its senotherapeutic role in a high risk population” (El Jurdi et al., Frontiers in Aging, 2025) (Frontiers)

Summary

Background & Motivation

  • Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy for many hematologic diseases, but it is associated with accelerated biological aging, increased cellular senescence, frailty, and long-term morbidity, due to intensive chemotherapy, radiation, and immune stressors. (Frontiers)
  • Sirolimus (rapamycin) is used in HCT settings, particularly for graft-versus-host disease (GVHD) prophylaxis. Separately, rapamycin is one of the best-studied gerotherapeutic / senotherapeutic candidates (i.e. interventions that slow aging or ameliorate senescence). The question: can sirolimus, administered in the transplant setting, also have a beneficial effect on cellular senescence markers in these high-risk patients? (Frontiers)
  • The authors designed a pilot / exploratory longitudinal study in HCT recipients to compare patients receiving sirolimus (Siro) vs cyclosporine (CSA) as GVHD prophylaxis, in terms of markers of senescence and systemic inflammatory signatures (SASP factors). (Frontiers)

Methods & Data

  • They enrolled umbilical cord blood transplant recipients under reduced-intensity conditioning for whom Siro or CSA prophylaxis was used, with otherwise identical conditioning regimens. (Frontiers)
  • They collected longitudinal peripheral blood mononuclear cells (PBMCs) and plasma samples at baseline, day 100 post-HCT, and one year post-HCT. (Frontiers)
  • In PBMCs, they measured expression (by qPCR) of canonical senescence markers p16^INK4a and p21^CIP1(normalized to 18S rRNA). (Frontiers)
  • In plasma, they quantified a panel of SASP (senescence-associated secretory phenotype) cytokines / factors via multiplex ELISA. (Frontiers)
  • They compared changes relative to baseline between the Siro and CSA groups. (Frontiers)

Key Findings & Interpretation

  • No statistically significant differences were observed in expression of p16^INK4a or p21^CIP1 between the sirolimus vs cyclosporine groups at day 100 or one year post-transplant. (Frontiers)
  • Similarly, no robust differences in circulating SASP factor levels (e.g. IL-1β, IL-6, IL-10, IL-12, etc.) reached significance. There were some non-significant trends (e.g. somewhat lower median expression of p16/p21 in the Siro group, and modest differences in some cytokines), but these did not cross statistical thresholds with the small sample. (Frontiers)
  • The authors conclude that, at the dosing regimens currently used for GVHD prophylaxis, sirolimus is unlikely to exert a strong senotherapeutic effect in this setting. They caution that any beneficial anti-senescence effects of sirolimus may only manifest within a narrower therapeutic window (dose, timing) than that used clinically in transplantation. (Frontiers)
  • They acknowledge limitations: small cohort, the use of blood cells (which may not reflect solid-organ or tissue senescent burden), potential timing issues, and lack of dose escalation / optimization. (Frontiers)

Novelty & Contributions

Although the study is relatively modest in scale and is partly negative (no strong differences found), it still brings a few novel / value-adding aspects:

  1. First in-human pilot in high-aging-risk setting
  • To my knowledge, this is one of the first prospective (or semi-prospective) human studies in a high–accelerated-aging context (post–HCT) that directly tests whether sirolimus used for standard clinical purposes might modulate molecular aging / senescence biomarkers.
  • Most prior work on rapamycin/sirolimus as a geroprotector has been in animal models or in healthy/elderly human volunteers (e.g. in immunosenescence). Applying it in a clinical transplantation cohort is novel.
  1. Longitudinal sampling & standardized comparison
  • The study design includes pre-HCT baseline, and serial follow-up at day 100 and one year, which allows intra-individual changes.
  • The side-by-side comparison of Siro vs CSA (two clinically used immunosuppressants) in a matched conditioning regimen context is a pragmatic way to evaluate possible “collateral” senotherapeutic benefit.
  1. Bridging transplant medicine and geroscience
  • The paper seeks to connect the fields of transplant immunology / clinical HCT with senescence / aging biology, highlighting that transplant survivors are a population with extreme “accelerated aging” burden and thus a potential target for senotherapeutic interventions.
  1. Negative / boundary result as informing design constraints
  • Even though the result is largely negative, that itself is informative: it suggests that standard dosing of sirolimus in HCT does not automatically confer anti-senescence effects, thereby constraining expectations for geroprotective off-targets in this context.
  • The authors’ framing about therapeutic windows (dose, timing, tissue specificity) is an important caution for the field.

Thus, the novelty is not in a startling new molecular mechanism, but in the first translational test (in a frail, aging-prone human cohort) of whether sirolimus acts as a senotherapeutic agent in a clinical immunosuppressive regimen.

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#2

I couldn’t find in the paper the dosing regimen, but got an answer from chatGPT:

In hematopoietic cell transplantation (HCT) — also known as hematopoietic stem cell transplantation (HSCT) — sirolimus (rapamycin) is widely used as part of GVHD (graft-versus-host disease) prophylaxis, typically in combination with a calcineurin inhibitor (e.g. tacrolimus or cyclosporine). The dosing depends on the transplant type (allogeneic vs. autologous), route, and co-medications.

Here’s a summary of the standard clinical dosing regimens used in HCT settings:

:pill: Typical Sirolimus Regimen for GVHD Prophylaxis (Adults)

1. Oral loading dose:

  • 12 mg orally on day −3 or day 0 (timing depends on center protocol).

2. Maintenance dose:

  • 4 mg orally once daily, starting the day after the loading dose.

3. Target trough levels:

  • 5–15 ng/mL (measured by LC–MS/MS or immunoassay).

4. Duration:

  • Continued for about 3 months post-transplant (until day +90), then tapered off if no GVHD develops.

5. Combination therapy:

  • Most regimens combine sirolimus + tacrolimus, sometimes with methotrexate (MTX) or mycophenolate mofetil (MMF).

    • Example: “Tacrolimus + sirolimus ± short-course methotrexate” is a common protocol in reduced-intensity conditioning (RIC) transplants.

:medical_symbol: Example: Dana-Farber / Brigham and Women’s Regimen

(Referenced in Cutler et al., Blood 2004;104:460–466 and Antin et al., Blood 2003;102:1604–1610)

Component Dose Notes
Sirolimus 12 mg PO loading dose on day −3, then 4 mg PO daily Target 5–15 ng/mL
Tacrolimus 0.02 mg/kg/day IV starting day −3, switched to PO when tolerated Target 5–10 ng/mL
Methotrexate 5–15 mg/m² IV on days +1, +3, +6, +11 Optional (depends on conditioning)

:petri_dish: Pharmacokinetics and Interactions

  • Half-life: ~60 hours → steady state in ~5–7 days.
  • Metabolism: CYP3A4 and P-gp substrate.
  • Interactions: Azoles (voriconazole, fluconazole) and macrolides (clarithromycin) markedly increase sirolimus levels; dose adjustments are essential.
  • Nephrotoxicity: Minimal alone, but synergistic with tacrolimus, so troughs must be closely monitored.

:woman_standing: Pediatric dosing (for completeness)

  • Loading: 3 mg/m² (max 6 mg) orally day −3.
  • Maintenance: 1 mg/m²/day (max 4 mg/day).
  • Target trough: 5–15 ng/mL.

:books: Key References

  1. Cutler C, et al. Blood 2004;104(2):460–466. DOI: 10.1182/blood-2004-02-0657
  2. Antin JH, et al. Blood 2003;102(5):1604–1610. DOI: 10.1182/blood-2003-02-0495
  3. Armand P, et al. Biol Blood Marrow Transplant 2008;14(9):919–926.
  4. Kim SJ, et al. Bone Marrow Transplant 2010;45:1289–1296.
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