Most Human Rejuvenation Could Be Achieved By Targeting The Epigenome

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George Church is a Professor of Genetics at Harvard Medical School and a leading voice in geroscience – the study of ageing and the fundamental processes that drive it. He’s responsible for many studies investigating interventions that could one day be used to slow the ageing process in humans. He recently gave an interview with lifespan.io about some of his recent research as well as the future of geroscience. Here’s a summary of some of the key points.

Two gene therapies that improve mouse survival

• George Church was recently involved in a paper in which researchers used gene therapy to increase the expression of two proteins in mice: telomerase reverse transcriptase (which lengthens telomeres) and follistatin (which promotes muscle growth and repair among other things).
• They found that these treatments extended median lifespan by 41.4% and 32.5%, respectively.
• It’s not clear exactly why follistatin had such a large effect. It may be largely related to reduced muscle wasting and implications for cancer.
• One of the things that set this study apart was the use of cytomegalovirus to deliver the gene therapy. This is a virus that can carry a very large cargo.
• Despite this, the combination of telomerase and follistatin wasn’t tested, mainly due to monetary constraints.
• Since telomerase and follistatin act mostly independently, seeing what they do in combination will be exciting.
• We know that prolonged doses of telomerase can increase cancer risk. However, this could be mitigated in humans through intermittent dosing and through introduction of extra copies of protective genes.

Partial reprogramming via gene therapy improves mouse survival

• In another recent preprint study from Rejuvenate Bio, researchers used gene therapy to partially reprogram cells into a more youthful state.
• This involves delivering genes for factors that erase certain epigenetic changes associated with ageing.
• The treatment increased the median mouse lifespan by 109%.
• This is particularly impressive given that the treatment occurred at age 124 weeks, which is old for a mouse.

Theories of ageing: damage vs epigenetics

• One camp believes that ageing happens due to damage to DNA, proteins and so on, and that this damage would need to be actively repaired by rejuvenation therapies.
• Another believes that most ageing is due to epigenetic changes, and that if you can erase these changes, the cell is capable of repairing almost all damage by itself.
• Church believes in a hybrid model, but thinks that most work can be done epigenetically, a lot of it via delivering factors/gene therapies into the bloodstream.

Moving from animals to humans

• Rather than moving straight from mice to humans, Rejuvenate Bio are choosing to develop a veterinary product for dogs first.
• Dogs develop many similar diseases to humans, and we can use dogs to test whether a therapy can hit multiple diseases at once.
• Animal clinical trials are much faster, and it’s valuable to have more than one before moving to humans.
• To move to humans with a gene therapy, you use the human versions of the same genes. You may also need to change the vector.

Marketing anti-ageing supplements in early research stages

• We should be cautious about supplements that have not gone through clinical trials.
• A clinical trial demonstrating effectiveness in one age-related disease doesn’t mean a supplement is ‘anti-ageing’.
• Some supplements are detrimental if taken for prolonged periods of time.
• There’s a lot of placebo effect and wishful thinking when it comes to longevity supplements.

The future of geroscience

• We need to hit all ten ageing pathways.
• The fastest way to test hypotheses about slowing ageing is using gene therapy – it takes a few weeks to go from a new research article to mouse experiments.
• We’ve accumulated enough knowledge to start moving towards combination anti-ageing treatments, provided they are first tested in animals.