Downregulation of the Apelinergic Axis Accelerates Aging, whereas Its Systemic Restoration Improves the Mammalian Healthspan

Rahul Rai; Asish K. Ghosh; Mesut Eren; Alexander R. Mackie; Daniel C. Levine; So Youn Kim; Jonathan Cedernaes; Veronica Ramirez; Daniele Procissi; Layton H. Smith; Teresa K. Woodruff; Joseph Bass; Douglas E. Vaughan

doi:10.1016/j.celrep.2017.10.057

Downregulation of the Apelinergic Axis Accelerates Aging, whereas Its Systemic Restoration Improves the Mammalian Healthspan

Rahul Rai, Asish K. Ghosh, Mesut Eren, Alexander R. Mackie, Daniel C. Levine, So Youn Kim, Jonathan Cedernaes, Veronica Ramirez, Daniele Procissi, Layton H. Smith, Teresa K. Woodruff, Joseph Bass, Douglas E. Vaughan^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

67 Scopus citations

Abstract

Aging drives the occurrence of numerous diseases, including cardiovascular disease (CVD). Recent studies indicate that blood from young mice reduces age-associated pathologies. However, the “anti-aging” factors in juvenile circulation remain poorly identified. Here, we characterize the role of the apelinergic axis in mammalian aging and identify apelin as an anti-aging factor. The expression of apelin (apln) and its receptor (aplnr) exhibits an age-dependent decline in multiple organs. Reduced apln signaling perturbs organismal homeostasis; mice harboring genetic deficiency of aplnr or apln exhibit enhanced cardiovascular, renal, and reproductive aging. Genetic or pharmacological abrogation of apln signaling also induces cellular senescence mediated, in part, by the activation of senescence-promoting transcription factors. Conversely, restoration of apln in 15-month-old wild-type mice reduces cardiac hypertrophy and exercise-induced hypertensive response. Additionally, apln-restored mice exhibit enhanced vigor and rejuvenated behavioral and circadian phenotypes. Hence, a declining apelinergic axis promotes aging, whereas its restoration extends the murine healthspan. Rai et al. identify an anti-aging role of the endogenous apelinergic axis. They show that the apelin-apelin receptor axis is downregulated with age and that its absence accelerates the onset and progression of aging. Additionally, restoration of apelin extends the murine healthspan.

Original language	English (US)
Pages (from-to)	1471-1480
Number of pages	10
Journal	Cell Reports
Volume	21
Issue number	6
DOIs	https://doi.org/10.1016/j.celrep.2017.10.057
State	Published - Nov 7 2017

Funding

We thank Dr. Thomas Quertermous (Stanford, CA) for providing us with apln −/− and aplnr −/− mice. We acknowledge the support of two NHLBI grants awarded to D.E.V.: 2R01HL051387-18A1 and PPG HLI08795 . A.K.G. was supported by AHA grant 16GRNT31130010 . D.C.L., J.C., and J.B. were supported by NIDDK grant 5R01DK100814 awarded to J.B. S.-Y.K. and T.K.W. were supported by the Center for Reproductive Health After Disease grant P50HD076188 from the NIH-NCTRI .

Keywords

aging
apelin
APJ
aplnr
senescence

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2017.10.057

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Rai, R., Ghosh, A. K., Eren, M., Mackie, A. R., Levine, D. C., Kim, S. Y., Cedernaes, J., Ramirez, V., Procissi, D., Smith, L. H., Woodruff, T. K., Bass, J., & Vaughan, D. E. (2017). Downregulation of the Apelinergic Axis Accelerates Aging, whereas Its Systemic Restoration Improves the Mammalian Healthspan. Cell Reports, 21(6), 1471-1480. https://doi.org/10.1016/j.celrep.2017.10.057

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title = "Downregulation of the Apelinergic Axis Accelerates Aging, whereas Its Systemic Restoration Improves the Mammalian Healthspan",

abstract = "Aging drives the occurrence of numerous diseases, including cardiovascular disease (CVD). Recent studies indicate that blood from young mice reduces age-associated pathologies. However, the “anti-aging” factors in juvenile circulation remain poorly identified. Here, we characterize the role of the apelinergic axis in mammalian aging and identify apelin as an anti-aging factor. The expression of apelin (apln) and its receptor (aplnr) exhibits an age-dependent decline in multiple organs. Reduced apln signaling perturbs organismal homeostasis; mice harboring genetic deficiency of aplnr or apln exhibit enhanced cardiovascular, renal, and reproductive aging. Genetic or pharmacological abrogation of apln signaling also induces cellular senescence mediated, in part, by the activation of senescence-promoting transcription factors. Conversely, restoration of apln in 15-month-old wild-type mice reduces cardiac hypertrophy and exercise-induced hypertensive response. Additionally, apln-restored mice exhibit enhanced vigor and rejuvenated behavioral and circadian phenotypes. Hence, a declining apelinergic axis promotes aging, whereas its restoration extends the murine healthspan. Rai et al. identify an anti-aging role of the endogenous apelinergic axis. They show that the apelin-apelin receptor axis is downregulated with age and that its absence accelerates the onset and progression of aging. Additionally, restoration of apelin extends the murine healthspan.",

keywords = "aging, apelin, APJ, aplnr, senescence",

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Rai, R, Ghosh, AK, Eren, M, Mackie, AR, Levine, DC, Kim, SY, Cedernaes, J, Ramirez, V, Procissi, D, Smith, LH, Woodruff, TK, Bass, J & Vaughan, DE 2017, 'Downregulation of the Apelinergic Axis Accelerates Aging, whereas Its Systemic Restoration Improves the Mammalian Healthspan', Cell Reports, vol. 21, no. 6, pp. 1471-1480. https://doi.org/10.1016/j.celrep.2017.10.057

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T1 - Downregulation of the Apelinergic Axis Accelerates Aging, whereas Its Systemic Restoration Improves the Mammalian Healthspan

AU - Rai, Rahul

AU - Ghosh, Asish K.

AU - Eren, Mesut

AU - Mackie, Alexander R.

AU - Levine, Daniel C.

AU - Kim, So Youn

AU - Cedernaes, Jonathan

AU - Ramirez, Veronica

AU - Procissi, Daniele

AU - Smith, Layton H.

AU - Woodruff, Teresa K.

AU - Bass, Joseph

AU - Vaughan, Douglas E.

PY - 2017/11/7

Y1 - 2017/11/7

N2 - Aging drives the occurrence of numerous diseases, including cardiovascular disease (CVD). Recent studies indicate that blood from young mice reduces age-associated pathologies. However, the “anti-aging” factors in juvenile circulation remain poorly identified. Here, we characterize the role of the apelinergic axis in mammalian aging and identify apelin as an anti-aging factor. The expression of apelin (apln) and its receptor (aplnr) exhibits an age-dependent decline in multiple organs. Reduced apln signaling perturbs organismal homeostasis; mice harboring genetic deficiency of aplnr or apln exhibit enhanced cardiovascular, renal, and reproductive aging. Genetic or pharmacological abrogation of apln signaling also induces cellular senescence mediated, in part, by the activation of senescence-promoting transcription factors. Conversely, restoration of apln in 15-month-old wild-type mice reduces cardiac hypertrophy and exercise-induced hypertensive response. Additionally, apln-restored mice exhibit enhanced vigor and rejuvenated behavioral and circadian phenotypes. Hence, a declining apelinergic axis promotes aging, whereas its restoration extends the murine healthspan. Rai et al. identify an anti-aging role of the endogenous apelinergic axis. They show that the apelin-apelin receptor axis is downregulated with age and that its absence accelerates the onset and progression of aging. Additionally, restoration of apelin extends the murine healthspan.

AB - Aging drives the occurrence of numerous diseases, including cardiovascular disease (CVD). Recent studies indicate that blood from young mice reduces age-associated pathologies. However, the “anti-aging” factors in juvenile circulation remain poorly identified. Here, we characterize the role of the apelinergic axis in mammalian aging and identify apelin as an anti-aging factor. The expression of apelin (apln) and its receptor (aplnr) exhibits an age-dependent decline in multiple organs. Reduced apln signaling perturbs organismal homeostasis; mice harboring genetic deficiency of aplnr or apln exhibit enhanced cardiovascular, renal, and reproductive aging. Genetic or pharmacological abrogation of apln signaling also induces cellular senescence mediated, in part, by the activation of senescence-promoting transcription factors. Conversely, restoration of apln in 15-month-old wild-type mice reduces cardiac hypertrophy and exercise-induced hypertensive response. Additionally, apln-restored mice exhibit enhanced vigor and rejuvenated behavioral and circadian phenotypes. Hence, a declining apelinergic axis promotes aging, whereas its restoration extends the murine healthspan. Rai et al. identify an anti-aging role of the endogenous apelinergic axis. They show that the apelin-apelin receptor axis is downregulated with age and that its absence accelerates the onset and progression of aging. Additionally, restoration of apelin extends the murine healthspan.

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Downregulation of the Apelinergic Axis Accelerates Aging, whereas Its Systemic Restoration Improves the Mammalian Healthspan

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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