Anti-ageing research under the spotlight

Monday, 25 February, 2019

Anti-ageing research under the spotlight

Two separate studies published recently have been investigating ways to suppress signs of ageing, which could eventually lead to extended lifespans in humans.

One of the research groups, from the US Salk Institute for Biological Studies, has highlighted a novel CRISPR/Cas9 genome-editing therapy that can suppress the accelerated ageing observed in mice with Hutchinson-Gilford progeria syndrome, a rare genetic disorder that also afflicts humans. Published in the journal Nature Medicine, their work provides important insight into the molecular pathways involved in accelerated ageing, as well as how to reduce toxic proteins via gene therapy.

“Ageing is a complex process in which cells start to lose their functionality, so it is critical for us to find effective ways to study the molecular drivers of ageing,” said Juan Carlos Izpisua Belmonte, senior author of the paper. “Progeria is an ideal ageing model because it allows us to devise an intervention, refine it and test it again quickly.”

With an early onset and fast progression, progeria is caused by a mutation in the LMNA gene, with patients showing signs of ageing including DNA damage, cardiac dysfunction and dramatically shortened life span. The LMNA gene normally produces two similar proteins inside a cell: lamin A and lamin C. Progeria shifts the production of lamin A to progerin — a shortened, toxic form of lamin A that accumulates with age and is exacerbated in those with progeria.

“Our goal was to diminish the toxicity from the mutation of the LMNA gene that leads to accumulation of progerin inside the cell,” said co-first author Hsin-Kai Liao. “We reasoned that progeria could be treated by CRISPR/Cas9-targeted disruption of both lamin A and progerin.”

The researchers utilised the CRISPR/Cas9 system to deliver the gene therapy into the cells of the progeria mouse model expressing Cas9. An adeno-associated virus (AAV) was injected containing two synthetic guide RNAs and a reporter gene. The guide RNA ushers the Cas9 protein to a specific location on the DNA where it can make a cut to render lamin A and progerin nonfunctional, without disrupting lamin C. The reporter helps researchers track the tissues that were infected with the AAV.

Two months after the delivery of the therapy, the mice were stronger and more active, with improved cardiovascular health. They showed decreased degeneration of a major arterial blood vessel and delayed onset of bradycardia (an abnormally slow heart rate) — two issues commonly observed in progeria and old age. Overall, the treated progeria mice had activity levels similar to normal mice, and their lifespan increased by roughly 25% — and the researchers are confident that with more efficient viruses, they will be able to increase lifespan even further.

The results suggest that targeting lamin A and progerin using a CRISPR/Cas9 system can dramatically improve the physiological health and life span of progeria mice. They thus provide a significant new understanding of how scientists may eventually be able to target molecular drivers of ageing in humans, particularly given that there is currently no cure for progeria.

“This is the first time a gene-editing therapy has been applied to treat progeria syndrome,” Izpisua Belmonte said. “It will need some refinements, but it has far fewer negative effects compared to other options available. This is an exciting advancement for the treatment of progeria.”

Meanwhile, scientists at Japan’s Osaka University have been researching autophagy — an important biological recycling mechanism that is used to maintain homeostasis (balance or equilibrium) within all types of animal tissue. Many studies have attempted to understand the relationship between the reduction of autophagy and progression of ageing in animals; however, none have provided a clear explanation until now.

In 2009, an Osaka research team led by Tamotsu Yoshimori identified Rubicon as a protein factor that suppresses autophagy by controlling a specific step in this pathway. This time, the team found that Rubicon expression levels increased in an age-related manner in worm, fly and mouse tissues, publishing their findings in Nature Communications.

Autophagy allows degradation of damaged cellular components and helps to avoid the onset of a variety of diseases related to cellular stress and dysfunction, including cancer, neurodegenerative diseases and metabolic syndromes. Reduced autophagy has recently been linked to progression of ageing in animals. While a variety of methods can increase autophagy in aged animals, thereby slowing the ageing process, there has been no definite finding regarding the underlying cause of naturally reduced autophagy.

“Rubicon has been linked to inhibition of the autophagic process, and knockout of Rubicon in mice helped to mitigate autophagy-related liver diseases,” Yoshimori said. “Therefore, we suspected that Rubicon may directly affect ageing through its interaction with autophagy.”

In the latest study, increased levels of Rubicon were found in tissues from multiple aged model organisms (worms, flies and mice). When the researchers suppressed Rubicon expression, all model organisms demonstrated increased autophagy activity, which led to improvement of multiple age-related factors and slightly increased lifespan in worms and flies.

“Our analyses revealed that Rubicon suppression in model organisms led to reduction of age-associated motor decline, as well as reduction of fibrosis,” said Shuhei Nakamura, lead author on the study. “Importantly, we found that Rubicon suppression enabled aged mice to resist attempts to induce Parkinson’s disease.”

The findings in this study suggest that, because elevated levels of Rubicon lead to reduced autophagy in aged animals, suppression of Rubicon may be critical in extending healthy lifespan in humans.

Image credit: ©Syda Productions/Dollar Photo Club

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