Aging is characterized by a progressive decline of physiological function accompanied by increased incidence of age-related disease. The accumulation of senescent cells is emerging as an important driving factor of the aging process. Senescent cells do not divide, are viable and metabolically active, but have altered physiology. In a study of endothelial cells (which line the inside of blood vessels), University of Exeter’s Professor Lorna Harries and colleagues tested three compounds designed to target mitochondria, and found each produced a 40-50% drop in the number of senescent cells. They also identified two splicing factors (a component of cells) that play a key role in when and how endothelial cells become senescent.
Cellular senescence in human cells. Image credit: Eva Latorre.
“As human bodies age, they accumulate senescent cells that do not function as well as younger cells. This is not just an effect of aging — it’s a reason why we age,” Professor Harries said.
“Our compounds have the potential to tweak the mechanisms by which this aging of cells happens.”
In a 2017 study, Professor Harries and co-authors demonstrated a new way to rejuvenate senescent cells in the laboratory.
However, the new research looked at precisely targeting and rejuvenating mitochondria in these old cells.
Each one of our genes is capable of making more than one product, and splicing factors are the genes that make the decision about which of these products are made.
In the new study, using novel chemicals, the team was able to very specifically target two splicing factors (SRSF2 or HNRNPD) that play a key role in determining how and why our cells change with advancing age.
“Nearly half of the aged cells we tested showed signs of rejuvenating into young cell models,” Professor Harries said.
The researchers tested three different compounds (AP39, AP123 and RT01) and found each produced a 40-50% drop in the number of senescent blood vessel cells.
“Our compounds provide mitochondria in cells with an alternative fuel to help them function properly,” said University of Exeter’s Professor Matt Whiteman, co-author of the study.
“Many disease states can essentially be viewed as accelerated aging, and keeping mitochondria healthy helps either prevent or, in many cases using animal models, reverse this.”
“Our current study shows that splicing factors play a key role in determining how our compounds work.”
The findings are published in the journal Aging.
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Eva Latorre et al. 2018. Mitochondria-targeted hydrogen sulfide attenuates endothelial senescence by selective induction of splicing factors HNRNPD and SRSF2. Aging 10 (7); doi: 10.18632/aging.101500
