Small extracellular vesicles from young plasma reverse age-related functional declines by improving mitochondrial energy metabolism

Abstract

Recent investigations into heterochronic parabiosis have unveiled robust rejuvenating effects of young blood on aged tissues. However, the specific rejuvenating mechanisms remain incompletely elucidated. Here we demonstrate that small extracellular vesicles (sEVs) from the plasma of young mice counteract pre-existing aging at molecular, mitochondrial, cellular and physiological levels. Intravenous injection of young sEVs into aged mice extends their lifespan, mitigates senescent phenotypes and ameliorates age-associated functional declines in multiple tissues. Quantitative proteomic analyses identified substantial alterations in the proteomes of aged tissues after young sEV treatment, and these changes are closely associated with metabolic processes. Mechanistic investigations reveal that young sEVs stimulate PGC-1α expression in vitro and in vivo through their miRNA cargoes, thereby improving mitochondrial functions and mitigating mitochondrial deficits in aged tissues. Overall, this study demonstrates that young sEVs reverse degenerative changes and age-related dysfunction, at least in part, by stimulating PGC-1α expression and enhancing mitochondrial energy metabolism.

References 82

1. 1.

   Campisi J. Aging, cellular senescence, and cancer. Annu. Rev. Physiol. 2013;75:685-705.

   Not in our library10.1146/annurev-physiol-030212-183653

2. 2.

   Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153:1194-1217.

   Not in our library10.1016/j.cell.2013.05.039

3. 3.

   Bayersdorf, R. & Schumacher, B. Recent advances in understanding the mechanisms determining longevity. F1000Res.8 F1000 Faculty Rev-1403 (2019).

   Not in our library10.12688/f1000research.19610.1

4. 4.
   Getting Old through the Blood: Circulating Molecules in Aging and Senescence of Cardiovascular Regenerative Cells · 2017

   Not checked
5. 5.

   Conboy MJ, Conboy IM, Rando TA. Heterochronic parabiosis: historical perspective and methodological considerations for studies of aging and longevity. Aging Cell. 2013;12:525-530.

   Not in our library10.1111/acel.12065

6. 6.

   Kheifets V, Braithwaite SP. Plasma-based strategies for therapeutic modulation of brain aging. Neurotherapeutics. 2019;16:675-684.

   Not in our library10.1007/s13311-019-00746-z

7. 7.

   Khoury R, Ghossoub E. Young blood products: emerging treatment for Alzheimer’s disease? Neural Regen. Res. 2018;13:624-627.

   Not in our library10.4103/1673-5374.230277

8. 8.

   Ma J, et al. Circulating factors in young blood as potential therapeutic agents for age-related neurodegenerative and neurovascular diseases. Brain Res. Bull. 2019;153:15-23.

   Not in our library10.1016/j.brainresbull.2019.08.004

9. 9.

   Castellano JM, et al. Human umbilical cord plasma proteins revitalize hippocampal function in aged mice. Nature. 2017;544:488-492.

   Not in our library10.1038/nature22067

10. 10.

    Khrimian L, et al. Gpr158 mediates osteocalcin’s regulation of cognition. J. Exp. Med. 2017;214:2859-2873.

    Not in our library10.1084/jem.20171320

11. 11.

    Kourembanas S. Exosomes: vehicles of intercellular signaling, biomarkers, and vectors of cell therapy. Annu. Rev. Physiol. 2015;77:13-27.

    Not in our library10.1146/annurev-physiol-021014-071641

12. 12.

    von Zglinicki T, et al. Frailty in mouse ageing: a conceptual approach. Mech. Ageing Dev. 2016;160:34-40.

    Not in our library10.1016/j.mad.2016.07.004

13. 13.

    Whitehead JC, et al. A clinical frailty index in aging mice: comparisons with frailty index data in humans. J. Gerontol. Ser. A Biol. Sci. Med. Sci. 2014;69:621-632.

    Not in our library10.1093/gerona/glt136

14. 14.

    Pino V, Sanz A, Valdes N, Crosby J, Mackenna A. The effects of aging on semen parameters and sperm DNA fragmentation. JBRA Assist. Reprod. 2020;24:82-86.

    Not in our library10.5935/1518-0557.20190058

15. 15.

    Schefer V, Talan MI. Oxygen consumption in adult and AGED C57BL/6J mice during acute treadmill exercise of different intensity. Exp. Gerontol. 1996;31:387-392.

    Not in our library10.1016/0531-5565(95)02032-2

16. 16.

    Dai D-F, Rabinovitch PS, Ungvari Z. Mitochondria and cardiovascular aging. Circ. Res. 2012;110:1109-1124.

    Not in our library10.1161/circresaha.111.246140

17. 17.

    Grodzicki T, Michalewicz L, Messerli FH. Aging and essential hypertension: effect of left ventricular hypertrophy on cardiac function. Am. J. Hypertens. 1998;11:425-429.

    Not in our library10.1016/s0895-7061(97)00500-1

18. 18.

    Baldock PAJ, Need AG, Moore RJ, Durbridge TC, Morris HA. Discordance between bone turnover and bone loss: effects of aging and ovariectomy in the rat. J. Bone Miner. Res. 1999;14:1442-1448.

    Not in our library10.1359/jbmr.1999.14.8.1442

19. 19.

    Byun, M. S. et al. Heterogeneity of regional brain atrophy patterns associated with distinct progression rates in Alzheimer’s disease. PLoS ONE10, e0142756 (2015).

    Not in our library10.1371/journal.pone.0142756

20. 20.

    Barreto G, Huang TT, Giffard RG. Age-related defects in sensorimotor activity, spatial learning, and memory in C57BL/6 mice. J. Neurosurg. Anesthesiol. 2010;22:214-219.

    Not in our library10.1097/ana.0b013e3181d56c98

21. 21.

    Ryall JG, Schertzer JD, Lynch GS. Cellular and molecular mechanisms underlying age-related skeletal muscle wasting and weakness. Biogerontology. 2008;9:213-228.

    Not in our library10.1007/s10522-008-9131-0

22. 22.

    Villeda SA, et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat. Med. 2014;20:659-663.

    Not in our library10.1038/nm.3569

23. 23.

    Lee BY, et al. Senescence-associated β-galactosidase is lysosomal β-galactosidase. Aging Cell. 2006;5:187-195.

    Not in our library10.1111/j.1474-9726.2006.00199.x

24. 24.

    Chen J, et al. Contribution of p16INK4a and p21CIP1 pathways to induction of premature senescence of human endothelial cells: permissive role of p53. Am. J. Physiol. Heart Circ. Physiol. 2006;290:H1575-H1586.

    Not in our library10.1152/ajpheart.00364.2005

25. 25.

    Kamal, N. S. M., Safuan, S., Shamsuddin, S. & Foroozandeh, P. Aging of the cells: insight into cellular senescence and detection methods. Eur. J. Cell Biol. 99, 151108 (2020).

    Not in our library10.1016/j.ejcb.2020.151108

26. 26.

    Chandrasekaran A, Idelchik MdPS, Melendez JA. Redox control of senescence and age-related disease. Redox Biol. 2017;11:91-102.

    Not in our library10.1016/j.redox.2016.11.005

27. 27.

    Ott C, et al. Role of advanced glycation end products in cellular signaling. Redox Biol. 2014;2:411-429.

    Not in our library10.1016/j.redox.2013.12.016

28. 28.

    Safaiyan S, et al. Age-related myelin degradation burdens the clearance function of microglia during aging. Nat. Neurosci. 2016;19:995-998.

    Not in our library10.1038/nn.4325

29. 29.

    Lane RK, Hilsabeck T, Rea SL. The role of mitochondrial dysfunction in age-related diseases. Biochim. Biophys. Acta. 2015;1847:1387-1400.

    Not in our library10.1016/j.bbabio.2015.05.021

30. 30.

    Bratic A, Larsson N-G. The role of mitochondria in aging. J. Clin. Invest. 2013;123:951-957.

    Not in our library10.1172/jci64125

31. 31.

    Rato L, et al. Pre-diabetes alters testicular PGC1-α/SIRT3 axis modulating mitochondrial bioenergetics and oxidative stress. Biochim. Biophys. Acta. 2014;1837:335-344.

    Not in our library10.1016/j.bbabio.2013.12.008

32. 32.

    Simsek-Duran, F. et al. Age-associated metabolic and morphologic changes in mitochondria of individual mouse and hamster oocytes. PLoS ONE8, e64955 (2013).

    Not in our library10.1371/journal.pone.0064955

33. 33.

    Capetanaki Y, Milner DJ, Weitzer G. Desmin in muscle formation and maintenance: knockouts and consequences. Cell Struct. Funct. 1997;22:103-116.

    Not in our library10.1247/csf.22.103

34. 34.

    Hutter E, Renner K, Jansen-Durr P, Gnaiger E. Biphasic oxygen kinetics of cellular respiration and linear oxygen dependence of antimycin A inhibited oxygen consumption. Mol. Biol. Rep. 2002;29:83-87.

    Not in our library10.1023/a:1020322922732

35. 35.

    Robbins PD, Morelli AE. Regulation of immune responses by extracellular vesicles. Nat. Rev. Immunol. 2014;14:195-208.

    Not in our library10.1038/nri3622

36. 36.

    Guo SC, et al. Exosomes derived from platelet-rich plasma promote the re-epithelization of chronic cutaneous wounds via activation of YAP in a diabetic rat model. Theranostics. 2017;7:81-96.

    Not in our library10.7150/thno.16803

37. 37.

    Zhang, W. et al. Cancer-derived small extracellular vesicles: emerging biomarkers and therapies for pancreatic ductal adenocarcinoma diagnosis/prognosis and treatment. J. Nanobiotechnology20, 446 (2022).

    Not in our library10.1186/s12951-022-01641-0

38. 38.

    Garcia-Martin R, et al. MicroRNA sequence codes for small extracellular vesicle release and cellular retention. Nature. 2022;601:446-451.

    Not in our library10.1038/s41586-021-04234-3

39. 39.

    Chen X, Liang H, Zhang J, Zen K, Zhang CY. Secreted microRNAs: a new form of intercellular communication. Trends Cell Biol. 2012;22:125-132.

    Not in our library10.1016/j.tcb.2011.12.001

40. 40.

    Wenz T. PGC-1α activation as a therapeutic approach in mitochondrial disease. IUBMB Life. 2009;61:1051-1062.

    Not in our library10.1002/iub.261

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