Senolytic drugs boost key protective protein

Date:
March 15, 2022
Source:
Mayo Clinic
Summary:
Researchers say senolytic drugs can boost a key protein in the
body that protects older people against aspects of aging and a
range of diseases.

Their findings demonstrate this in mice and human studies.



FULL STORY ==========================================================================
Mayo Clinic researchers say senolytic drugs can boost a key protein in
the body that protects older people against aspects of aging and a range
of diseases.

Their findings, which are published ineBioMedicine demonstrate this in
mice and human studies.


========================================================================== Senolytics developed at Mayo Clinic and given once clear the bloodstream
of senescent or "zombie" cells. These cells contribute to multiple
diseases and negative aspects of aging. This study shows that the removal
of senescent cells significantly boosts the production of a protective
protein called a-klotho.

"We show that there is an avenue for an orally active, small-molecule
approach to increase this beneficial protein and also to amplify the
action of senolytic drugs," says James Kirkland, M.D., Ph.D., a Mayo
Clinic internist and senior author of the study.

The researchers first showed that senescent cells decrease levels of
a-klotho in three types of human cells: umbilical vein endothelial
cells, kidney cells and brain cells. They also demonstrated that using
the senolyitics desatinib plus quercitin in three types of mice that
a-klotho was increased. And then after administering desatinib plus
quercitin in clinical trial participants with idiopathic pulmonary
fibrosis, that a-klotho also increased.

"We also are first to link the potential impact of fat-resident senescent
cells on brain a-klotho," says Yi Zhu, Ph.D., a Mayo Clinic physiologist
and biomedical engineer, and first author of the study. "This may open
another avenue to investigate the impact of peripheral senescent cells
on brain aging." The protein a-klotho is important to maintaining good
health, as it tends to decrease with age, and especially decreases
in multiple diseases, including Alzheimer's, diabetes and kidney
disease. Animal studies have shown that decreasing a-klotho in mice
shortens life span and increasing a-klotho in mice by inserting a gene
that causes its production increases life span by 30%.

Discovering ways to increase a-klotho in humans has been a major
research goal, but that has been difficult because of its size and
instability. Introducing it directly is problematic, as it would have
to be administered into a vein instead of by mouth.

This study shows that senolytics, which can be administered orally,
increase a- klotho in humans with idiopathic pulmonary fibrosis, a senescence-associated disease that leads to frailty, serious breathing difficulties and death.

The study was supported by the National Institute of Health, the
Translational Geroscience Network, Robert and Arlene Kogod, the Connor
Group, Robert J. and Theresa W. Ryan, and the Noaber Foundation.

The other authors are Yi Zhu, Ph.D.; Larissa Prata, Ph.D.; Erin Wissler
Gerdes; Jair Machado Espindola Netto, Ph.D.; Tamar Pirtskhalava, Ph.D.;
Nino Giorgadze; Utkarsh Tripathi; Christina Inman; Kurt Johnson;
Ailing Xue; Allyson Palmer, M.D., Ph.D.; Tingjun Chen, M.D., Ph.D.;
Kalli Schaefer; Jun Chen, Ph.D.; Sundeep Khosla, M.D.; Diana Jurk, Ph.D.; Marissa Schafer, Ph.D.; and Tamar Tchkonia, Ph.D. -- all of Mayo Clinic
-- and Jamie Justice, Ph.D., and Stephen Kritchevsky, Ph.D., Wake Forest
School of Medicine, and Anoop Nambiar, M.D., and Nicolas Musi, M.D.,
University of Texas.


========================================================================== Story Source: Materials provided by Mayo_Clinic. Original written by
Robert Nellis. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Yi Zhu, Larissa G.P. Langhi Prata, Erin O. Wissler Gerdes,
Jair Machado
Espindola Netto, Tamar Pirtskhalava, Nino Giorgadze, Utkarsh
Tripathi, Christina L. Inman, Kurt O. Johnson, Ailing Xue,
Allyson K. Palmer, Tingjun Chen, Kalli Schaefer, Jamie N. Justice,
Anoop M. Nambiar, Nicolas Musi, Stephen B. Kritchevsky, Jun Chen,
Sundeep Khosla, Diana Jurk, Marissa J. Schafer, Tamar Tchkonia,
James L. Kirkland. Orally-active, clinically-translatable senolytics
restore a-Klotho in mice and humans.

eBioMedicine, 2022; 103912 DOI: 10.1016/j.ebiom.2022.103912 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220315141757.htm

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