Longevity

French Scientists Show Cellular Rejuvenation Prolongs Lifespan and Mitigates Age-Related Disease

Researchers in France moderately prolong the lifespan of mice and reverse skin, bone, lung, and kidney aging with cellular reprogramming — a new technology that rejuvenates cells.

By Daniel R. Miranda, Ph.D.

Key Points: 

  • Mouse lifespan is extended by approximately 15% with cellular reprogramming.
  • Cellular reprogrammed mice have less fat, more lean mass, and younger skin. 
  • Arthritis, osteoporosis, and other age-related diseases are marked down by cellular reprogramming.

While breaking the spell of aging is a ceaseless endeavor, scientists are getting closer to making age reversal a reality with cellular reprogramming. Cellular reprogramming has captured the imaginations of many for its remarkable age-reversing capabilities, including reversing the biological age of human cells by about 30 years. Now, scientists are perfecting the craft by honing in on how to reverse the age of mice. 

As reported in Aging Cell, Alle and colleagues from the University of Montpellier in France report that cellular reprogramming increases the lifespan and improves the fitness of aged mice. In addition to increasing the lifespan of naturally aging mice, cellular reprogramming increases the lifespan and rejuvenates multiple organs in a mouse model for accelerated aging. This includes the rejuvenation of the metabolic system, skin, bone, lung, spleen, and kidney.

Cellular Rejuvenation Prolongs Lifespan & Reverses Aging

With only a few (2 ½) weeks of cellular reprogramming, Alle and colleagues were able to increase the lifespan of mice. The French scientists induced whole-body cellular reprogramming in the mice when they were 2-months-old, equivalent to about 20 years old in humans. While normal mice lived to be a little over 70 years old in human years, reprogrammed mice lived for the equivalent of nearly 100 human years. Furthermore, skin cells from these reprogrammed mice had fewer senescent cells — cells associated with accelerated aging

cellular programming extends lifespan and reduces senescent cells
(Alle et al., 2022 | Aging Cell) Cellular Reprogramming Prolongs Mouse Lifespan and Reduces Senescent Cells. Compared to normal mice (CTL), mice that have been reprogrammed with 0.5 mg/ml of doxycycline for 2.5 weeks (0.5 mg/ml 2.5 weeks) survive approximately 15% longer. Reprogrammed (DOX) mice also have less senescent (SA-βGAL) cells.

Nowadays, scientists can activate genes in mice by putting a chemical called doxycycline (DOX) in their drinking water. That is, mice can be genetically engineered to harbor genes containing a DOX “on-switch.” When these mice drink DOX, the switch is flipped on to activate DOX-controlled genes. Alle and colleagues used the DOX system to turn on Yamanaka factors (Oct3/4, Sox2, Klf4, c-Myc), a set of four genes that are the basis for cellular reprogramming and trick cells into regressing to an earlier developmental stage.

Like they did in naturally aging mice, Alle and colleagues induced cellular reprogramming in a mouse model for accelerated aging. In response to reprogramming, the lifespans of the accelerated aging mice were prolonged. Furthermore, the reprogrammed mice did not lose lean mass or gain fat mass like unprogrammed mice, demonstrating improvements in metabolism. Reprogramming also increased skin thickness by 40% and other skin layers by 120%, giving the skin more youthful properties.

cellular programming reverses metabolic and skin aging
(Alle et al., 2022 | Aging Cell) Cellular Reprogramming Reverses Metabolic and Skin Aging. Compared to normal mice (CTL), reprogrammed mice (DOX) lose less lean mass and gain less fat mass (left), indicative of improved metabolism. Reprogramming also thickens the skin (right).

Once the age accelerated mice ceased to live, Alle and collages harvested their organs to examine markers of disease. They found that cellular reprogramming mitigated much of the organ deterioration associated with human age-related diseases. For example, bone deterioration, which is associated with arthritis and osteoporosis, was largely prevented by reprogramming. 

Fibrosis —characterized by inflammation and scarring — is the primary cause of age-related deterioration of organs like the lungs, kidneys, and liver. Fibrosis of the lungs is associated with a disease called idiopathic pulmonary fibrosis, which often results in respiratory failure. Alle and colleagues showed that cellular reprogramming decreased lung fibrosis. There were also signs of reduced fibrosis in the kidney and improvements in the structure of the spleen, suggesting the age reversal of multiple organs.

The Future of Anti-Aging Therapeutics?

Cellular reprogramming has previously been shown to prolong the lifespan of mice, however, these mice were extremely age accelerated mice. By showing that reprogramming can extend the lifespan of normal mice, Alle and colleagues reinforce the feasibility of cellular reprogramming as an anti-aging therapy. Also supporting this, other studies have shown that reprogramming can rejuvenate organs like the skin and kidneys of naturally aged mice. However, at least one study has shown that reprogramming can lead to cancer. Thus, cellular reprogramming studies are not yet ready for humans, but may be in the future.

Source

Alle Q, Le Borgne E, Bensadoun P, Lemey C, Béchir N, Gabanou M, Estermann F, Bertrand-Gaday C, Pessemesse L, Toupet K, Desprat R, Vialaret J, Hirtz C, Noël D, Jorgensen C, Casas F, Milhavet O, Lemaitre JM. A single short reprogramming early in life initiates and propagates an epigenetically related mechanism improving fitness and promoting an increased healthy lifespan. Aging Cell. 2022 Oct 17:e13714. doi: 10.1111/acel.13714. Epub ahead of print. PMID: 36251933.

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