High throughput screening identifies molecules that reduce cellular
stress
The technique could help researchers find drugs that improve health and lengthen life

Date:
October 5, 2020
Source:
Michigan Medicine - University of Michigan
Summary:
A new article describes the discovery of several promising small
molecules that appear to reduce cellular stress in mouse skin
cells and could lengthen life.



FULL STORY ==========================================================================
For many, getting older can unfortunately mean an increased risk of
illness from cardiovascular disease to cancer. University of Michigan scientists are actively researching the biological underpinnings of
aging with the aim of developing interventions that could potentially
help people live longer, healthier lives.


==========================================================================
A new paper in the journal Science Advances describes the discovery of
several promising small molecules that appear to reduce cellular stress
in mouse skin cells and could lengthen life.

"Cellular stress resistance appears to be a common feature of long-lived organisms, such as invertebrates and mice," says the paper's lead author
David Lombard, M.D., Ph.D., associate professor of pathology. Lombard
is part of a multidisciplinary group at U-M's Paul F. Glenn Center for
Aging. Recent research from colleague and fellow study author Richard
Miller, M.D., Ph.D., found several promising drugs, including rapamycin,
a cancer drug, and acarbose, a diabetes drug, that extended life in mice.

The new study, which uses high throughput screening, a technique that
allows for the examination of hundreds of compounds at once, gets around
some of the limitations posed by mouse studies.

"Mice live on average three years, which makes using them for longevity
studies time-consuming and expensive," Lombard explains. By using cells
to examine how a cell responds to stress, they hope to develop a proxy
system with which to look at aging.

For the study, mouse skin cells were exposed to three types of
environmental stress: a toxic herbicide called paraquat, the heavy metal cadmium and methyl methansulfonate, which damages DNA. After treatment
with more than 4500 compounds, the team identified hundreds of small
molecules that conferred some degree of protection against one or more
of the stressors. The team then focused on eight compounds for a closer examination of how they worked at the molecular level.

Lombard explains that two candidates, AEG 3482 and cardamonin (found
in spices such as cardamom), appeared to activate the Nrf2/SKN-1
pathway. Previous research has shown that this pathway helps cells
resist stress and is implicated in the life-lengthening effects of
several other interventions in C.

elegans, a worm frequently used for aging studies, and can even extend
the lifespan of male mice.

Comparing their findings to a different study of longevity in C. elegans,
they found some of the same compounds that protected worms from stress
were of the same class as those that their team identified as effective
in mouse cells.

The team notes that their method has limitations. For example, they found
that rapamycin and acarbose, previously shown to extend life in mice,
did not protect against the stressors they used. And, says Lombard, a
lot more work needs to occur before the findings can be extrapolated to
humans. "I think the bottom line is we're fairly different than worms
and flies, and some of these drugs have similar effects in different
organisms, but it's not a one to one relationship." Lombard says the
promise of the method is its ability to find interesting drugs for
follow up, especially to study their mechanism of action. "I don't
think any are ready for lifespan studies, but what we've identified is
an interesting group of compounds that have some intriguing effects in
cells and in invertebrates."

========================================================================== Story Source: Materials provided by
Michigan_Medicine_-_University_of_Michigan. Original written by Kelly
Malcom. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. David B. Lombard, William J. Kohler, Angela H. Guo, Christi Gendron,
Melissa Han, Weiqiao Ding, Yang Lyu, Tsui-Ting Ching, Feng-Yung
Wang, Tuhin S. Chakraborty, Zaneta Nikolovska-Coleska, Yuzhu
Duan, Thomas Girke, Ao-Lin Hsu, Scott D. Pletcher, Richard
A. Miller. High-throughput small molecule screening reveals
Nrf2-dependent and -independent pathways of cellular stress
resistance. Science Advances, 2020; 6 (40): eaaz7628 DOI:
10.1126/sciadv.aaz7628 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/10/201005112142.htm

--- up 6 weeks, 6 hours, 50 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1337:3/111)