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MTOR Inhibition Leads to 30% Life Extension in Progeric Mice

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Posted on Sep 09, 2021, 1 p.m.

Researchers have created a new mouse model for studying Hutchinson-Gilford progeria syndrome (HGPS) and achieved 30% lifespan extension in these animals by genetically downregulating mTOR [1].

HGPS: accelerated aging

HGPS, sometimes referred to just as ‘progeria’, is a rare disease that affects one in 4 to 8 million people and is widely thought to be a form of accelerated aging. The analogy is not perfect, but HGPS patients do seem to accumulate many age-related types of damage very quickly, and the average lifespan among them is just 14.5 years. Most HGPS patients die of cardiovascular diseases, the number one age-related killer.

HGPS is genetic, but not hereditary: it is caused by a spontaneous mutation in a parent’s germline, and affected offspring mostly do not live long enough to pass the mutation down to the next generation. The mutation results in incorrect (“cryptic”) splicing that, instead of producing the protein lamin A, churns out a faulty and truncated peptide chain that folds into the toxic protein progerin.

Lamins participate in the formation of the nuclear lamina, a thin inner layer of the nuclear wall that enhances its structural integrity. Progerin interferes with this process, which results in deformed nuclei. HGPS is currently considered incurable.

Just how much does HGPS resemble normal aging? The mechanism of the disease’s progression remains unclear, with one of the possible culprits being DNA instability, a major driver of normal aging. Progerin production has also been linked to telomere attrition, another hallmark of aging. As one study notes, natural aging and the premature aging in HGPS are mediated by similar signaling pathways [2]. “Most features of natural aging are found in HGPS”, this paper says. “While the primary cause of HGPS is quite different, the secondary downstream causes and their consequences at the organismal level are very similar to natural aging. Thus, HGPS indeed represents bona fide accelerated aging, not merely a semblance of aging.” Aging acceleration in HGPS has also been confirmed by methylation clocks.

Mice that produce the human protein

Animal models of HGPS are important both for developing cures for HGPS and for studying normal aging, since the latter, thankfully, takes a long time to play out. The problem with murine models of HGPS has been that a similar mutation in the homologous mouse gene does not fully recapitulate the symptoms and progression of human HGPS.

In this new study, the researchers, instead of manipulating mouse genes, introduced a human mutated (progerin-producing) gene carried by a bacterial artificial chromosome (BAC). This means that the genetically engineered mice produce both normal lamins and human progerin, similarly to human HGPS patients, who are always heterozygous for the disease. Mice with two copies of BAC recapitulate many HGPS symptoms, most notably cardiovascular ones. Since this model produces the human version of the protein, it might be more useful for developing anti-HGPS drugs than previous models.

Having created their HGPS mouse model, the researchers tried a treatment: genetic downregulation of the mechanistic target of rapamycin (mTOR) pathway. This is a major nutrient sensing regulator, and its suppression has been shown to prolong lifespan and healthspan in numerous model organisms, including primates [3]. Rapamycin, one of the most promising compounds in geroscience, does just that, and is currently in human trials crowdfunded by LEAF. A human trial of the rapamycin analog everolimus for people with HGPS is also underway, with results expected within a year. Another way to downregulate mTOR is via caloric restriction, a potent anti-aging intervention.

Long live the mTOR-deficient mice!

The researchers created genetically engineered mice with impaired mTOR production and cross-bred them with their HGPS-prone mice. The offspring enjoyed an average 30% increase in lifespan over HGPS-prone mice with normal mTOR levels. On the other hand, some symptoms of HGPS were not affected in the new model. The authors of this study are unsure about the mechanism that led to such a substantial lifespan increase and conclude that more research is needed. They also note that mTOR takes part in two different protein complexes – mTORC1 and mTORC2 – with only the first one being directly affected by rapamycin and its analogs [4]. The genetic approach that the scientists took alters the production of both complexes and thus might not perfectly mimic the effects of known mTOR inhibitors.

Conclusion

This research resulted in the creation of a new mouse HGPS model which might help in finding treatments for this horrible disease. On top of that, the study expands our understanding of the link between HGPS and normal aging and suggests an interesting possible treatment option: downregulation of mTOR. Even though there is an ongoing everolimus trial in HGPS patients, the genetic approach might eventually be proven superior.

This article was written by Arkadi Mazin on Lifespan.io

As with anything you read on the internet, this article should not be construed as medical advice; please talk to your doctor or primary care provider before making any changes to your wellness routine.

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Materials provided by:

https://www.lifespan.io/news/mtor-inhibition-leads-to-30-life-extension-in-progeric-mice/

https://www.lifespan.io/profile/arkadi-mazin/

https://doi.org/10.1111/acel.13457

https://clinicaltrials.gov/ct2/show/NCT02579044

[1] Cabral, W. A., Tavarez, U. L., Beeram, I., Yeritsyan, D., Boku, Y. D., Eckhaus, M. A., … & Collins, F. S. (2021). Genetic reduction of mTOR extends lifespan in a mouse model of Hutchinson-Gilford Progeria syndrome. Aging Cell, e13457.

[2] Ashapkin, V. V., Kutueva, L. I., Kurchashova, S. Y., & Kireev, I. I. (2019). Are There Common Mechanisms Between the Hutchinson–Gilford Progeria Syndrome and Natural Aging?. Frontiers in genetics, 10, 455.

[3] Papadopoli, D., Boulay, K., Kazak, L., Pollak, M., Mallette, F. A., Topisirovic, I., & Hulea, L. (2019). mTOR as a central regulator of lifespan and aging. F1000Research, 8.

[4] Schreiber, K. H., Ortiz, D., Academia, E. C., Anies, A. C., Liao, C. Y., & Kennedy, B. K. (2015). Rapamycin-mediated mTORC 2 inhibition is determined by the relative expression of FK 506-binding proteins. Aging cell, 14(2), 265-273.

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