Assessing Gene Therapy to Upregulate Three Longevity-Associated Genes in Mice

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Today’s open access research materials report on results obtained in mice using gene therapy to upregulates protein production of several longevity-associated genes. As expected from prior research into these genes and their influence on the operation of metabolism, health is improved in mouse models of age-related disease. As might also be expected based on past results, some combinations are not effective for reasons that remain to be explored: metabolism is complicated, and pulling on levers and turning dials rarely does exactly what was expected.

Evolution does not produce optimal organisms, as seen from the perspective of the individual. This is well illustrated in mice, where any number of single gene alterations, even just dialing up or down the amount of protein produced over time, leads to better health, less disease, longer lives. Why haven’t any of these small alterations taken place via random mutation and thereafter prospered and spread through the species over the course of evolutionary time? Because evolutionary competition in the wild is a race to the bottom, in which lineages engineered for early life success at the cost of later life collapse tend to outcompete those with a biochemistry more friendly to the individual.

This applies as much to humans as it does to mice. There are variant human genes that offer much reduced risk of cardiovascular disease, found in a small fraction of the population. Why don’t we all have those variants? Because evolution doesn’t place much emphasis on late life health and survival. Further, many of the alterations known to improve health and longevity in mice should be expected to at least improve health in humans. So at some point in the years ahead, the use of gene therapies to improve human metabolism so as to reduce age-related disease and improve longevity will be a going concern. It will start with therapies for adults that don’t integrate with the genome and are not passed on to children, and at some point, once the will is there, the medical community will start to engineer better human lineages.

This class of approach most likely won’t be the most important road to increased longevity in the near future, however. The gains that can be achieved through periodic repair of the human biochemistry that we have today should be far greater than those produced by engineering an improved biochemistry that is more resilient to damage. We know that a youthful mammalian biochemistry works pretty well, and the differences between youth and age emerge from forms of cell and tissue damage, such as accumulation of senescent cells and persistent metabolic waste products. To the degree that the research community can repair that damage, rejuvenation will be the outcome. Yes, that repair may take the form of gene therapies, such as to deliver novel enzymes capable of breaking down metabolic waste, but this is a very different approach in comparison to the type of gene therapy tested in the research noted here, which is an attempt to shift the operation of cellular metabolism into a more resilient state, not to repair damage.

Combination gene therapy treats multiple age-related diseases in mice

Researchers honed in on three genes that had previously been shown to confer increased health and lifespan benefits when their expression was modified in genetically engineered mice: FGF21, sTGFβR2, and αKlotho. They hypothesized that providing extra copies of those genes to non-engineered mice via gene therapy would similarly combat age-related diseases and confer health benefits. The team created separate gene therapy constructs for each gene using the AAV8 serotype as a delivery vehicle, and injected them into mouse models of obesity, type II diabetes, heart failure, and renal failure both individually and in combination with the other genes to see if there was a synergistic beneficial effect.

FGF21 alone caused complete reversal of weight gain and type II diabetes in obese, diabetic mice following a single gene therapy administration, and its combination with sTGFβR2 reduced kidney atrophy by 75% in mice with renal fibrosis. Heart function in mice with heart failure improved by 58% when they were given sTGFβR2 alone or in combination with either of the other two genes, showing that a combined therapeutic treatment of FGF21 and sTGFβR2 could successfully treat all four age-related conditions, therefore improving health and survival. Administering all three genes together resulted in slightly worse outcomes, likely from an adverse interaction between FGF21 and αKlotho, which remains to be studied.

A single combination gene therapy treats multiple age-related diseases

Comorbidity is common as age increases, and currently prescribed treatments often ignore the interconnectedness of the involved age-related diseases. The presence of any one such disease usually increases the risk of having others, and new approaches will be more effective at increasing an individual’s health span by taking this systems-level view into account. In this study, we developed gene therapies based on 3 longevity associated genes: fibroblast growth factor 21 (FGF21), αKlotho, soluble form of mouse transforming growth factor-β receptor 2 (sTGFβR2). The gene therapies were delivered using adeno-associated viruses, and we explored their ability to mitigate 4 age-related diseases: obesity, type II diabetes, heart failure, and renal failure.

Individually and combinatorially, we applied these therapies to disease-specific mouse models and found that this set of diverse pathologies could be effectively treated and in some cases, even reversed with a single dose. We observed a 58% increase in heart function in ascending aortic constriction ensuing heart failure, a 38% reduction in α-smooth muscle actin (αSMA) expression, and a 75% reduction in renal medullary atrophy in mice subjected to unilateral ureteral obstruction and a complete reversal of obesity and diabetes phenotypes in mice fed a constant high-fat diet. Crucially, we discovered that a single formulation combining 2 separate therapies into 1 was able to treat all 4 diseases. These results emphasize the promise of gene therapy for treating diverse age-related ailments and demonstrate the potential of combination gene therapy that may improve health span and longevity by addressing multiple diseases at once.

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