. 2024 Feb;46(1):795-816.

doi: 10.1007/s11357-023-01011-0. Epub 2023 Dec 2.

Astaxanthin and meclizine extend lifespan in UM-HET3 male mice; fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate do not significantly affect lifespan in either sex at the doses and schedules used

David E Harrison^#¹, Randy Strong^#^{2

3

4

5}, Peter Reifsnyder⁶, Nadia Rosenthal⁶, Ron Korstanje⁶, Elizabeth Fernandez^{2

3

5}, Kevin Flurkey⁶, Brett C Ginsburg⁷, Meredith D Murrell⁷, Martin A Javors⁷, Marisa Lopez-Cruzan⁷, James F Nelson^{2

8}, Bradley J Willcox⁹, Richard Allsopp⁹, David M Watumull^{10

11}, David G Watumull^{10

11}, Gino Cortopassi¹², James L Kirkland¹³, Tamar Tchkonia¹³, Young Geun Choi¹⁴, Matthew J Yousefzadeh¹⁴, Paul D Robbins¹⁴, James R Mitchell¹⁵, Murat Acar¹⁶, Ethan A Sarnoski¹⁷, Michael R Bene¹⁸, Adam Salmon^{2

3

4

18}, Navasuja Kumar¹⁹, Richard A Miller^#²⁰

Affiliations

¹ The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA. david.harrison@jax.org.
² Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center, San Antonio, TX, USA.
³ Education, and Clinical Center, Geriatric Research, San Antonio, TX, USA.
⁴ Research Service, South Texas Veterans Health Care System, San Antonio, TX, USA.
⁵ Department of Pharmacology, The University of Texas Health Science Center, San Antonio, TX, USA.
⁶ The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA.
⁷ Department of Psychiatry, The University of Texas Health Science Center, San Antonio, TX, USA.
⁸ Department of Physiology, The University of Texas Health Sciences Center, San Antonio, TX, USA.
⁹ John A. Burns School of Medicine, University of Hawai'I at Mānoa, Honolulu, HI, USA.
¹⁰ , Cardax, Honolulu, HI, USA.
¹¹ AX3 Life, Honolulu, HI, USA.
¹² Department of Molecular Biosciences, University of California, Davis, CA, USA.
¹³ Mayo Clinic, Rochester, MN, USA.
¹⁴ University of Minnesota, Minneapolis, MN, USA.
¹⁵ Harvard School of Public Health, Boston, MA, USA.
¹⁶ Department of Basic Medical Sciences, School of Medicine, Koç University, 34450, Istanbul, Turkey.
¹⁷ Department of Internal Medicine, Yale University, New Haven, CT, USA.
¹⁸ Department of Molecular Medicine, The University of Texas Health Sciences Center, San Antonio, TX, USA.
¹⁹ Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
²⁰ Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor, MI, USA.

^# Contributed equally.

PMID: 38041783
PMCID: PMC10828146
DOI: 10.1007/s11357-023-01011-0

Astaxanthin and meclizine extend lifespan in UM-HET3 male mice; fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate do not significantly affect lifespan in either sex at the doses and schedules used

David E Harrison et al. Geroscience. 2024 Feb.

. 2024 Feb;46(1):795-816.

doi: 10.1007/s11357-023-01011-0. Epub 2023 Dec 2.

Authors

Affiliations

¹ The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA. david.harrison@jax.org.
² Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center, San Antonio, TX, USA.
³ Education, and Clinical Center, Geriatric Research, San Antonio, TX, USA.
⁴ Research Service, South Texas Veterans Health Care System, San Antonio, TX, USA.
⁵ Department of Pharmacology, The University of Texas Health Science Center, San Antonio, TX, USA.
⁶ The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA.
⁷ Department of Psychiatry, The University of Texas Health Science Center, San Antonio, TX, USA.
⁸ Department of Physiology, The University of Texas Health Sciences Center, San Antonio, TX, USA.
⁹ John A. Burns School of Medicine, University of Hawai'I at Mānoa, Honolulu, HI, USA.
¹⁰ , Cardax, Honolulu, HI, USA.
¹¹ AX3 Life, Honolulu, HI, USA.
¹² Department of Molecular Biosciences, University of California, Davis, CA, USA.
¹³ Mayo Clinic, Rochester, MN, USA.
¹⁴ University of Minnesota, Minneapolis, MN, USA.
¹⁵ Harvard School of Public Health, Boston, MA, USA.
¹⁶ Department of Basic Medical Sciences, School of Medicine, Koç University, 34450, Istanbul, Turkey.
¹⁷ Department of Internal Medicine, Yale University, New Haven, CT, USA.
¹⁸ Department of Molecular Medicine, The University of Texas Health Sciences Center, San Antonio, TX, USA.
¹⁹ Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
²⁰ Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor, MI, USA.

^# Contributed equally.

PMID: 38041783
PMCID: PMC10828146
DOI: 10.1007/s11357-023-01011-0

Abstract

In genetically heterogeneous (UM-HET3) mice produced by the CByB6F1 × C3D2F1 cross, the Nrf2 activator astaxanthin (Asta) extended the median male lifespan by 12% (p = 0.003, log-rank test), while meclizine (Mec), an mTORC1 inhibitor, extended the male lifespan by 8% (p = 0.03). Asta was fed at 1840 ± 520 (9) ppm and Mec at 544 ± 48 (9) ppm, stated as mean ± SE (n) of independent diet preparations. Both were started at 12 months of age. The 90th percentile lifespan for both treatments was extended in absolute value by 6% in males, but neither was significant by the Wang-Allison test. Five other new agents were also tested as follows: fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate. None of these increased lifespan significantly at the dose and method of administration tested in either sex. Amounts of dimethyl fumarate in the diet averaged 35% of the target dose, which may explain the absence of lifespan effects. Body weight was not significantly affected in males by any of the test agents. Late life weights were lower in females fed Asta and Mec, but lifespan was not significantly affected in these females. The male-specific lifespan benefits from Asta and Mec may provide insights into sex-specific aspects of aging.

Keywords: 4-Phenylbutyrate (PBA); Astaxanthin (Asta); Dimethyl Fumarate (DMF); Fisetin (Fis); Heterogeneous mice; Lifespan; Meclizine (Mec); Mycophenolic acid (MPA); SG1002.

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Conflict of interest statement

The PIs and technicians at the sites doing and analyzing the aging studies had no conflicts of interest. DMW and DGW run Cardax, a pharmaceutical company that supplies Asta in a special form. Mayo Clinic holds patents on certain senolytic agents. None is currently licensed. TT holds shares from Unity Biotechnology. PDR is the cofounder of Itasca Therapeutics, a virtual startup to develop novel senotherapeutics.

Figures

**Fig. 1**
Lifespans of male HET3 mice fed Asta or MEC compared to controls

**Fig. 2**
Site-specific lifespan curves for controls. Site specific lifespan data were more variable than usual

**Fig. 3**
A Site-specific and pooled lifespan curves for drugs with no significant effects in HET3 males. B Site-specific and pooled lifespan curves for drugs with no significant effects in HET3 females

**Fig. 4**
Body weights over the lifespan. Body weights for the mice in Table 1

**Fig. 5**
The p16 mRNA senescent cell marker increases with age in HET3 mice, but no senescent cell markers are reduced by either fisetin diet

See this image and copyright information in PMC

References

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Astaxanthin and meclizine extend lifespan in UM-HET3 male mice; fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate do not significantly affect lifespan in either sex at the doses and schedules used

Affiliations

Astaxanthin and meclizine extend lifespan in UM-HET3 male mice; fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate do not significantly affect lifespan in either sex at the doses and schedules used

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Molecular Biology Databases