Stem cell therapy shows promise for reversing aging-related frailty in new clinical trial
Stem cells are gaining attention for their potential to treat leukemia, certain solid tumor cancers, and inherited metabolic disorders. Now, a clinical trial reports that a single dose can significantly improve physical strength and key signs of aging in older adults with frailty.
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Clinical and Translational ReportVolume 33, Issue 3p393-404.e4March 05, 2026
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Randomized phase 2b dose-escalation trial of stem cell therapy with laromestrocel for aging frailty
Jorge G. Ruiz1,2,17 ∙ Anthony A. Oliva, Jr.3,17 ∙ Kevin N. Ramdas3 ∙ … ∙ Zarin Zainul3 ∙ Brian G. Rash3 ∙ Joshua M. Hare3,16,19 [email protected] … Show more
Affiliations & Notes
1Memorial Healthcare System, Hollywood, FL, USA
2Florida Atlantic University Schmidt College of Medicine, Boca Raton, FL, USA
3Longeveron Inc., Miami, FL, USA
4Advanced Research for Health Improvement, LLC, Naples, FL, USA
5Clinical Research of South Florida, Coral Gables, FL, USA
6Panax Clinical Research, Miami Lakes, FL, USA
7Vista Health Research, LLC, Miami, FL, USA
8Clinical Physiology Associates, Ft. Myers, FL, USA
9Johns Hopkins University, Baltimore, MD, USA
10National Center for Geriatrics and Gerontology, Obu, Japan
11Sealy Center on Aging, University of Texas Medical Branch, Galveston, TX, USA
12Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
13Pharma Data Associates LLC, Piscataway, NJ, USA
14Miami VA Healthcare System Geriatric Research, Education and Clinical Center (GRECC), Miami, FL 33125, USA
15Provonix, Sewell, NJ 08080, USA
16Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
17
These authors contributed equally
18
Deceased
19
Lead contact
Article Info
Publication History:
Received September 7, 2025; Revised December 12, 2025; Accepted January 28, 2026; Published online February 25, 2026
DOI: 10.1016/j.stem.2026.01.017 External LinkAlso available on ScienceDirect External Link
Copyright: © 2026 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.
Published: February 25, 2026
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Highlights
•
Performance on the 6-minute walk test improved in a dose-response fashion
•
Improved 6-minute walk test distance correlated with patient-reported outcomes
•
The percentage of study subjects classified as frail decreased by month 9
•
Decreased soluble TIE2 in blood may reflect improved vascular function and inflammaging
Summary
Frailty, a syndrome that decreases healthspan in older individuals, lacks effective therapies. We conducted a randomized, dose-finding clinical trial to test whether human bone marrow-derived allogeneic mesenchymal stem cells (MSCs; laromestrocel) improve physical functioning and patient self-reported outcomes in ambulatory individuals with frailty (ClinicalTrials.gov #NCT03169231; N = 148). Laromestrocel infusion results in clinically meaningful, dose- and time-dependent increases in the 6-min walk test (6MWT; primary endpoint) compared with placebo: 63.4 m (95% confidence interval [CI]: 17.1–109.6 m; p = 0.0077) at month 9 and 41.3 m (95% CI: −2.4–84.9 m; p = 0.0635) at month 6. Increased 6MWT distance correlates with PROMIS Physical Function score, and increasing doses of laromestrocel are associated with decreases in soluble (degraded) tyrosine kinase with immunoglobulin and epidermal growth factor homology domains (TIE2), the cognate receptor for the angiopoietins, identifying a potential biomarker of laromestrocel responsiveness. These findings identify a stem cell therapy approach for the management of patients with hypomobility and other features of aging frailty.
Graphical abstract
Keywords
- mesenchymal stem cell
- laromestrocel
- aging frailty
- cell therapy
- TIE2
- healthspan
- longevity
- inflammaging
- aging
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References
1.
Hoogendijk, E.O. ∙ Afilalo, J. ∙ Ensrud, K.E. …
Frailty: implications for clinical practice and public health
Lancet. 2019; 394:1365-1375
2.
Kim, D.H. ∙ Rockwood, K.
Frailty in Older Adults
N. Engl. J. Med. 2024; 391:538-548
3.
Suo, X. ∙ Li, L. ∙ Guo, J. …
Association of Frailty With Dementia and the Mediating Role of Brain Structure and Immunometabolic Signatures
Neurology. 2025; 105, e214199
4.
O’Caoimh, R. ∙ Sezgin, D. ∙ O’Donovan, M.R. …
Prevalence of frailty in 62 countries across the world: a systematic review and meta-analysis of population-level studies
Age Ageing. 2021; 50:96-104
5.
Howlett, S.E. ∙ Rutenberg, A.D. ∙ Rockwood, K.
The degree of frailty as a translational measure of health in aging
Nat. Aging. 2021; 1:651-665
6.
Boyle, P.A. ∙ Buchman, A.S. ∙ Barnes, L.L. …
Association between life space and risk of mortality in advanced age
J. Am. Geriatr. Soc. 2010; 58:1925-1930
7.
Xue, Q.L. ∙ Fried, L.P. ∙ Glass, T.A. …
Life-space constriction, development of frailty, and the competing risk of mortality: the Women’s Health And Aging Study I
Am. J. Epidemiol. 2008; 167:240-248
8.
May, D. ∙ Nayak, U.S. ∙ Isaacs, B.
The life-space diary: a measure of mobility in old people at home
Int. Rehabil. Med. 1985; 7:182-186
9.
Cohen, H.J. ∙ Smith, D. ∙ Sun, C.L. …
Frailty as determined by a comprehensive geriatric assessment-derived deficit-accumulation index in older patients with cancer who receive chemotherapy
Cancer. 2016; 122:3865-3872
10.
Mümken, S.A. ∙ Alonso-Perez, E. ∙ Haeger, C. …
Prevention of frailty in relation with social out-of-home activities in older adults: results from the Survey of Health, Ageing, and Retirement in Europe
Eur. J. Ageing. 2024; 21, 35
11.
Ankuda, C.K. ∙ Freedman, V.A. ∙ Covinsky, K.E. …
Population-Based Screening for Functional Disability in Older Adults
Innov. Aging. 2021; 5, igaa065
12.
Boxer, R. ∙ Kleppinger, A. ∙ Ahmad, A. …
The 6-minute walk is associated with frailty and predicts mortality in older adults with heart failure
Congest. Heart Fail. 2010; 16:208-213
13.
Harada, N.D. ∙ Chiu, V. ∙ Stewart, A.L.
Mobility-related function in older adults: assessment with a 6-minute walk test
Arch. Phys. Med. Rehabil. 1999; 80:837-841
14.
Walston, J. ∙ Bandeen-Roche, K. ∙ Buta, B. …
Moving Frailty Toward Clinical Practice: NIA Intramural Frailty Science Symposium Summary
J. Am. Geriatr. Soc. 2019; 67:1559-1564
15.
Bisset, E.S. ∙ Howlett, S.E.
The biology of frailty in humans and animals: Understanding frailty and promoting translation
Aging Med. (Milton). 2019; 2:27-34
16.
Franceschi, C. ∙ Campisi, J.
Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases
J. Gerontol. A Biol. Sci. Med. Sci. 2014; 69:S4-S9
17.
Ferrucci, L. ∙ Fabbri, E.
Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty
Nat. Rev. Cardiol. 2018; 15:505-522
18.
Li, X. ∙ Li, C. ∙ Zhang, W. …
Inflammation and aging: signaling pathways and intervention therapies
Signal Transduct. Target. Ther. 2023; 8:239
19.
Franceschi, C. ∙ Garagnani, P. ∙ Parini, P. …
Inflammaging: a new immune-metabolic viewpoint for age-related diseases
Nat. Rev. Endocrinol. 2018; 14:576-590
20.
Damluji, A.A. ∙ Chung, S.E. ∙ Xue, Q.L. …
Frailty and cardiovascular outcomes in the National Health and Aging Trends Study
Eur. Heart J. 2021; 42:3856-3865
21.
Buch, A. ∙ Carmeli, E. ∙ Boker, L.K. …
Muscle function and fat content in relation to sarcopenia, obesity and frailty of old age–An overview
Exp. Gerontol. 2016; 76:25-32
22.
Liu, L. ∙ Rando, T.A.
Manifestations and mechanisms of stem cell aging
J. Cell Biol. 2011; 193:257-266
23.
Matteini, F. ∙ Montserrat-Vazquez, S. ∙ Florian, M.C.
Rejuvenating aged stem cells: therapeutic strategies to extend health and lifespan
FEBS Lett. 2024; 598:2776-2787
24.
Ferrón, S. ∙ Mira, H. ∙ Franco, S. …
Telomere shortening and chromosomal instability abrogates proliferation of adult but not embryonic neural stem cells
Development. 2004; 131:4059-4070
25.
Cai, Y. ∙ Xiong, M. ∙ Xin, Z. …
Decoding aging-dependent regenerative decline across tissues at single-cell resolution
Cell Stem Cell. 2023; 30:1674-1691.e8
26.
Chambers, S.M. ∙ Shaw, C.A. ∙ Gatza, C. …
Aging hematopoietic stem cells decline in function and exhibit epigenetic dysregulation
PLOS Biol. 2007; 5, e201
27.
Pittenger, M.F. ∙ Discher, D.E. ∙ Péault, B.M. …
Mesenchymal stem cell perspective: cell biology to clinical progress
NPJ Regen. Med. 2019; 4, 22
28.
Oliva, A.A. ∙ McClain-Moss, L. ∙ Pena, A. …
Allogeneic mesenchymal stem cell therapy: A regenerative medicine approach to geroscience
Aging Med. (Milton). 2019; 2:142-146
29.
Thompson, M. ∙ Mei, S.H.J. ∙ Wolfe, D. …
Cell therapy with intravascular administration of mesenchymal stromal cells continues to appear safe: An updated systematic review and meta-analysis
EClinicalmedicine. 2020; 19, 100249
30.
Hare, J.M. ∙ Traverse, J.H. ∙ Henry, T.D. …
A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction
J. Am. Coll. Cardiol. 2009; 54:2277-2286
31.
Golpanian, S. ∙ El-Khorazaty, J. ∙ Mendizabal, A. …
Effect of aging on human mesenchymal stem cell therapy in ischemic cardiomyopathy patients
J. Am. Coll. Cardiol. 2015; 65:125-132
32.
Golpanian, S. ∙ DiFede, D.L. ∙ Khan, A. …
Allogeneic Human Mesenchymal Stem Cell Infusions for Aging Frailty
J. Gerontol. A Biol. Sci. Med. Sci. 2017; 72:1505-1512
33.
Tompkins, B.A. ∙ DiFede, D.L. ∙ Khan, A. …
Allogeneic Mesenchymal Stem Cells Ameliorate Aging Frailty: A Phase II Randomized, Double-Blind, Placebo-Controlled Clinical Trial
J. Gerontol. A Biol. Sci. Med. Sci. 2017; 72:1513-1522
34.
Golpanian, S. ∙ DiFede, D.L. ∙ Pujol, M.V. …
Rationale and design of the allogeneiC human mesenchymal stem cells (hMSC) in patients with aging fRAilTy via intravenoUS delivery (CRATUS) study: A phase I/II, randomized, blinded and placebo controlled trial to evaluate the safety and potential efficacy of allogeneic human mesenchymal stem cell infusion in patients with aging frailty
Oncotarget. 2016; 7:11899-11912
35.
Rash, B.G. ∙ Ramdas, K.N. ∙ Agafonova, N. …
Allogeneic mesenchymal stem cell therapy with laromestrocel in mild Alzheimer’s disease: a randomized controlled phase 2a trial
Nat. Med. 2025; 31:1257-1266
36.
Brody, M. ∙ Agronin, M. ∙ Herskowitz, B.J. …
Results and insights from a phase I clinical trial of Lomecel-B for Alzheimer’s disease
Alzheimers Dement. 2023; 19:261-273
37.
Yousefi, K. ∙ Ramdas, K.N. ∙ Ruiz, J.G. …
The Design and Rationale of a Phase 2b, Randomized, Double-Blinded, and Placebo-Controlled Trial to Evaluate the Safety and Efficacy of Lomecel-B in Older Adults with Frailty
J. Frailty Aging. 2022; 11:214-223
38.
Yuan, H.T. ∙ Khankin, E.V. ∙ Karumanchi, S.A. …
Angiopoietin 2 is a partial agonist/antagonist of Tie2 signaling in the endothelium
Mol. Cell. Biol. 2009; 29:2011-2022
39.
Fiedler, U. ∙ Reiss, Y. ∙ Scharpfenecker, M. …
Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation
Nat. Med. 2006; 12:235-239
40.
Fiedler, U. ∙ Krissl, T. ∙ Koidl, S. …
Angiopoietin-1 and angiopoietin-2 share the same binding domains in the Tie-2 receptor involving the first Ig-like loop and the epidermal growth factor-like repeats
J. Biol. Chem. 2003; 278:1721-1727
41.
Idowu, T.O. ∙ Etzrodt, V. ∙ Seeliger, B. …
Identification of specific Tie2 cleavage sites and therapeutic modulation in experimental sepsis
eLife. 2020; 9, e59520
42.
Findley, C.M. ∙ Mitchell, R.G. ∙ Duscha, B.D. …
Plasma levels of soluble Tie2 and vascular endothelial growth factor distinguish critical limb ischemia from intermittent claudication in patients with peripheral arterial disease
J. Am. Coll. Cardiol. 2008; 52:387-393
43.
Lee, K.W. ∙ Lip, G.Y.H. ∙ Blann, A.D.
Plasma angiopoietin-1, angiopoietin-2, angiopoietin receptor tie-2, and vascular endothelial growth factor levels in acute coronary syndromes
Circulation. 2004; 110:2355-2360
44.
Parikh, S.M.
Targeting Tie2 and the host vascular response in sepsis
Sci. Transl. Med. 2016; 8, 8
45.
Han, S. ∙ Lee, S.J. ∙ Kim, K.E. …
Amelioration of sepsis by TIE2 activation-induced vascular protection
Sci. Transl. Med. 2016; 8, 335ra55
46.
Jiang, L. ∙ Hu, X. ∙ Feng, Y. …
Reduction of renal interstitial fibrosis by targeting Tie2 in vascular endothelial cells
Pediatr. Res. 2024; 95:959-965
47.
Yan, F. ∙ Meng, X. ∙ Cheng, X. …
Potential role between inflammatory cytokines and Tie-2 receptor levels and clinical symptoms in patients with first-episode schizophrenia
BMC Psychiatry. 2023; 23, 538
48.
Scheufler, K.M. ∙ Drevs, J. ∙ van Velthoven, V. …
Implications of vascular endothelial growth factor, sFlt-1, and sTie-2 in plasma, serum and cerebrospinal fluid during cerebral ischemia in man
J. Cereb. Blood Flow Metab. 2003; 23:99-110
49.
Shoemaker, M.J. ∙ Curtis, A.B. ∙ Vangsnes, E. …
Clinically meaningful change estimates for the six-minute walk test and daily activity in individuals with chronic heart failure
Cardiopulm. Phys. Ther. J. 2013; 24:21-29
50.
Kwok, B.C. ∙ Pua, Y.H. ∙ Mamun, K. …
The minimal clinically important difference of six-minute walk in Asian older adults
BMC Geriatr. 2013; 13, 23
51.
Perera, S. ∙ Mody, S.H. ∙ Woodman, R.C. …
Meaningful change and responsiveness in common physical performance measures in older adults
J. Am. Geriatr. Soc. 2006; 54:743-749
52.
Yazdanyar, A. ∙ Aziz, M.M. ∙ Enright, P.L. …
Association Between 6-Minute Walk Test and All-Cause Mortality, Coronary Heart Disease-Specific Mortality, and Incident Coronary Heart Disease
J. Aging Health. 2014; 26:583-599
53.
Bohannon, R.W. ∙ Crouch, R.
Minimal clinically important difference for change in 6-minute walk test distance of adults with pathology: a systematic review
J. Eval. Clin. Pract. 2017; 23:377-381
54.
Rockwood, K. ∙ Song, X. ∙ MacKnight, C. …
A global clinical measure of fitness and frailty in elderly people
CMAJ. 2005; 173:489-495
55.
Sack, K.D. ∙ Kellum, J.A. ∙ Parikh, S.M.
The Angiopoietin-Tie2 Pathway in Critical Illness
Crit. Care Clin. 2020; 36:201-216
56.
Lozito, T.P. ∙ Jackson, W.M. ∙ Nesti, L.J. …
Human mesenchymal stem cells generate a distinct pericellular zone of MMP activities via binding of MMPs and secretion of high levels of TIMPs
Matrix Biol. 2014; 34:132-143
57.
Elliott, M.R. ∙ Koster, K.M. ∙ Murphy, P.S.
Efferocytosis Signaling in the Regulation of Macrophage Inflammatory Responses
J. Immunol. 2017; 198:1387-1394
58.
Cheung, T.S. ∙ Giacomini, C. ∙ Cereda, M. …
Apoptosis in mesenchymal stromal cells activates an immunosuppressive secretome predicting clinical response in Crohn’s disease
Mol. Ther. 2023; 31:3531-3544
59.
Galleu, A. ∙ Riffo-Vasquez, Y. ∙ Trento, C. …
Apoptosis in mesenchymal stromal cells induces in vivo recipient-mediated immunomodulation
Sci. Transl. Med. 2017; 9, eaam7828
60.
Rockwood, K. ∙ Mitnitski, A.
Frailty defined by deficit accumulation and geriatric medicine defined by frailty
Clin. Geriatr. Med. 2011; 27:17-26
61.
Juma, S. ∙ Taabazuing, M.M. ∙ Montero-Odasso, M.
Clinical Frailty Scale in an Acute Medicine Unit: a Simple Tool That Predicts Length of Stay
Can. Geriatr. J. 2016; 19:34-39
62.
Ritt, M. ∙ Ritt, J.I. ∙ Sieber, C.C. …
Comparing the predictive accuracy of frailty, comorbidity, and disability for mortality: a 1-year follow-up in patients hospitalized in geriatric wards
Clin. Interv. Aging. 2017; 12:293-304
63.
Cesari, M. ∙ Bernabei, R. ∙ Vellas, B. …
Challenges in the Development of Drugs for Sarcopenia and Frailty – Report from the International Conference on Frailty and Sarcopenia Research (ICFSR) Task Force
J. Frailty Aging. 2022; 11:135-142
64.
Egorin, M.J. ∙ Rosen, D.M. ∙ Sridhara, R. …
Plasma concentrations and pharmacokinetics of dimethylsulfoxide and its metabolites in patients undergoing peripheral-blood stem-cell transplants
J. Clin. Oncol. 1998; 16:610-615
65.
Cella, D. ∙ Yount, S. ∙ Rothrock, N. …
The Patient-Reported Outcomes Measurement Information System (PROMIS): progress of an NIH Roadmap cooperative group during its first two years
Med. Care. 2007; 45:S3-S11
66.
Born, J. ∙ Lange, T. ∙ Hansen, K. …
Effects of sleep and circadian rhythm on human circulating immune cells
J. Immunol. 1997; 158:4454-4464
67.
Bretz, F. ∙ Pinheiro, J.C. ∙ Branson, M.
Combining multiple comparisons and modeling techniques in dose-response studies
Biometrics. 2005; 61:738-748
68.
Menon, S.M. ∙ Zink, R.C.
Modern Approaches to Clinical Trials Using SAS: Classical, Adaptive, and Bayesian Methods.SAS Institute, 2015
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