Dietary supplementation of clinically utilized PI3K p110α inhibitor extends the lifespan of male and female mice

Journal article

Hedges, Christopher P., Shetty, Bhoopika, Broome, Sophie C., MacRae, Caitlin, Koutsifeli, Parisa, Buckels, Emma J., MacIndoe, C., Boix, Jordi, Tsiloulis, Thomas, Matthews, Brya G., Sinha, Sanjay, Arendse, Michael, Jaiswal, Jagdish K., Mellor, Kim M., Hickey, Anthony J. R., Shepherd, Peter R. and Merry, Troy L.. (2023). Dietary supplementation of clinically utilized PI3K p110α inhibitor extends the lifespan of male and female mice. Nature Aging. 3(2), pp. 162-172. https://doi.org/10.1038/s43587-022-00349-y
AuthorsHedges, Christopher P., Shetty, Bhoopika, Broome, Sophie C., MacRae, Caitlin, Koutsifeli, Parisa, Buckels, Emma J., MacIndoe, C., Boix, Jordi, Tsiloulis, Thomas, Matthews, Brya G., Sinha, Sanjay, Arendse, Michael, Jaiswal, Jagdish K., Mellor, Kim M., Hickey, Anthony J. R., Shepherd, Peter R. and Merry, Troy L.
Abstract

Diminished insulin and insulin-like growth factor-1 signaling extends the lifespan of invertebrates1,2,3,4; however, whether it is a feasible longevity target in mammals is less clear5,6,7,8,9,10,11,12. Clinically utilized therapeutics that target this pathway, such as small-molecule inhibitors of phosphoinositide 3-kinase p110α (PI3Ki), provide a translatable approach to studying the impact of these pathways on aging. Here, we provide evidence that dietary supplementation with the PI3Ki alpelisib from middle age extends the median and maximal lifespan of mice, an effect that was more pronounced in females. While long-term PI3Ki treatment was well tolerated and led to greater strength and balance, negative impacts on common human aging markers, including reductions in bone mass and mild hyperglycemia, were also evident. These results suggest that while pharmacological suppression of insulin receptor (IR)/insulin-like growth factor receptor (IGFR) targets could represent a promising approach to delaying some aspects of aging, caution should be taken in translation to humans.

Year2023
JournalNature Aging
Journal citation3 (2), pp. 162-172
PublisherNature Publishing Group
ISSN2662-8465
Digital Object Identifier (DOI)https://doi.org/10.1038/s43587-022-00349-y
PubMed ID37118113
Scopus EID2-s2.0-85146666146
Page range162-172
FunderHealth Research Council of New Zealand
Maurice Wilkins Centre
Publisher's version
License
All rights reserved
File Access Level
Controlled
Output statusPublished
Publication dates
Online23 Jan 2023
Publication process dates
Accepted02 Dec 2022
Deposited24 Apr 2025
Grant ID17/099
Additional information

© The Author(s), under exclusive licence to Springer Nature America, Inc. 2023.

Permalink -

https://acuresearchbank.acu.edu.au/item/91q97/dietary-supplementation-of-clinically-utilized-pi3k-p110-inhibitor-extends-the-lifespan-of-male-and-female-mice

Log in to edit

Restricted files

Publisher's version

  • 5
    total views
  • 0
    total downloads
  • 5
    views this month
  • 0
    downloads this month
These values are for the period from 19th October 2020, when this repository was created.

Export as

Related outputs

A role for β-catenin in diet-induced skeletal muscle insulin resistance
Mason, Stewart W. C., Dissanayake, Waruni C., Broome, Sophie C., Hedges, Christopher P., Peters, Wouter M., Gram, Martin, Rowlands, David S., Shepherd, Peter R. and Merry, Troy L.. (2023). A role for β-catenin in diet-induced skeletal muscle insulin resistance. Physiological Reports. 11(4), p. Article e15536. https://doi.org/10.14814/phy2.15536
Mitochondria-targeted antioxidant supplementation does not affect muscle soreness or recovery of maximal voluntary isometric contraction force following muscle-damaging exercise in untrained men : A randomized clinical trial
Broome, S. C., Atiola, R. D., Braakhuis, A. J., Mitchell, C. J. and Merry, T. L.. (2022). Mitochondria-targeted antioxidant supplementation does not affect muscle soreness or recovery of maximal voluntary isometric contraction force following muscle-damaging exercise in untrained men : A randomized clinical trial. Applied Physiology, Nutrition and Metabolism. 47(7), pp. 762-774. https://doi.org/10.1139/apnm-2021-0767
MitoQ supplementation augments acute exercise-induced increases in muscle PGC1α mRNA and improves training-induced increases in peak power independent of mitochondrial content and function in untrained middle-aged men
Broome, S. C., Pham, T., Braakhuis, A. J., Narang, R., Wang, H. W., Hickey, A. J. R., Mitchell, C. J. and Merry, T. L.. (2022). MitoQ supplementation augments acute exercise-induced increases in muscle PGC1α mRNA and improves training-induced increases in peak power independent of mitochondrial content and function in untrained middle-aged men. Redox Biology. 53, p. Article 102341. https://doi.org/10.1016/j.redox.2022.102341
Skeletal muscle NOX4 is required for adaptive responses that prevent insulin resistance
Xirouchaki, Chrysovalantou E., Jia, Yaoyao, McGrath, Meagan J., Greatorex, Spencer, Tran, Melanie, Merry, Troy L., Hong, Dawn, Eramo, Matthew J., Broome, Sophie C., Woodhead, Jonathan S. T., D'souza, Randall F., Gallagher, Jenny, Salimova, Ekaterina, Huang, Cheng, Schittenhelm, Ralf B., Sadoshima, Junichi, Watt, Matthew J., Mitchell, Christina A. and Tiganis, Tony. (2021). Skeletal muscle NOX4 is required for adaptive responses that prevent insulin resistance. Science Advances. 7(51), p. Article eabl4988. https://doi.org/10.1126/sciadv.abl4988
β-Catenin is required for optimal exercise- andcontraction-stimulated skeletal muscle glucose uptake
Masson, Stewart W. C., Woodhead, Jonathan S. T., D'Souza, Randall F., Broome, Sophie C., MacRae, Caitlin, Cho, Hyun C., Atiola, Robert D., Futi, Tumani, Dent, Jessica R., Shepherd, Peter R. and Merry, Troy L.. (2021). β-Catenin is required for optimal exercise- andcontraction-stimulated skeletal muscle glucose uptake. Journal of Physiology. 599(16), pp. 3897-3912. https://doi.org/10.1113/JP281352
Pre-exercise carbohydrate or protein ingestion influences substrate oxidation but not performance or hunger compared with cycling in the fasted state
Rothschild, Jeffrey A., Kilding, Andrew E., Broome, Sophie C., Stewart, Tom, Cronin, John B. and Plews, Daniel J.. (2021). Pre-exercise carbohydrate or protein ingestion influences substrate oxidation but not performance or hunger compared with cycling in the fasted state. Nutrients. 13(4), p. Article 1291. https://doi.org/10.3390/nu13041291
Mitochondria-targeted antioxidantsupplementation improves 8 km time trialperformance in middle-aged trained male cyclists
Broome, S. C., Braakhuis, A. J., Mitchell, C. J. and Merry, T. L.. (2021). Mitochondria-targeted antioxidantsupplementation improves 8 km time trialperformance in middle-aged trained male cyclists. Journal of the International Society of Sports Nutrition. 18(1), p. Article 58. https://doi.org/10.1186/s12970-021-00454-0
MitoQ and CoQ10 supplementation mildly suppresses skeletal muscle mitochondrial hydrogen peroxide levels without impacting mitochondrial function in middle‑aged men
Pham, Toan, MacRae, Caitlin L., Broome, Sophie C., D'Souza, Randall F., Narang, Ravi, Wang, Hsiang W., Mori, Trevor A., Hickey, Anthony J. R., Mitchell, Cameron J. and Merry, Troy L.. (2020). MitoQ and CoQ10 supplementation mildly suppresses skeletal muscle mitochondrial hydrogen peroxide levels without impacting mitochondrial function in middle‑aged men. European Journal of Applied Physiology. 120, pp. 1657-1669. https://doi.org/10.1007/s00421-020-04396-4
Mitochondria-targeted antioxidants and skeletal muscle function
Broome, Sophie, Woodhead, Jonathan and Merry, Troy. (2018). Mitochondria-targeted antioxidants and skeletal muscle function. Antioxidants. 7(8), p. Article 107. https://doi.org/10.3390/antiox7080107