Targeted Cellular Reprogramming Extends Lifespan in Mice

Researchers at Altos Labs, led by Dr. Juan Carlos Izpisua Belmonte, have achieved significant lifespan extension in male mice through targeted partial cellular reprogramming. Their work, published in Science Translational Medicine, demonstrates that the rejuvenation of stressed and senescent cells can lead to substantial health improvements and extended lifespan in aging mice[^1].

Background: Cellular Reprogramming and Partial Rejuvenation

Cellular reprogramming has been a major focus in aging research since its discovery nearly two decades ago. Unlike full reprogramming that induces pluripotency, partial reprogramming retains cell identity while promoting cellular rejuvenation. This approach is pursued by various companies, including Altos Labs, founded by Jeff Bezos and Yuri Milner with a $3 billion investment.

Altos Labs has assembled notable figures in the longevity field, including Steve Horvath, Morgan Levin, and Dr. Belmonte. Dr. Belmonte was the first to show that partial reprogramming can extend lifespan in fast-aging progeroid mice[^2]. The new research aims to bring partial reprogramming closer to clinical application by specifically targeting senescent cells.

OSK Factors and Selective Targeting

The researchers used three of the original Yamanaka factors: OCT4 (O), SOX2 (S), and KLF4 (K), collectively known as OSK, while omitting the fourth factor c-Myc to improve safety and reduce cellular stress[^3]. The novelty of the study lies in targeting only damaged cells—specifically stressed and senescent cells—across various tissues rather than all cells.

To achieve this targeting, the team used the Cdkn2a promoter, which is active in stressed and senescent cells. The viral vector was designed to express OSK only when the promoter is active, thus selectively reprogramming only those cells.

Lifespan Extension in Progeroid and Aged Mice

Experiment 1: Progeroid Mice

The team initially tested the therapy on Hutchinson-Guilford progeria syndrome mice, which experience accelerated aging. The results demonstrated:

• 40% increase in median lifespan.
• 32% increase in maximal lifespan.
• Improvements in body weight, activity levels, and reduced inflammation.

As a control, an anti-inflammatory agent targeting NF-κB was used, which yielded a smaller increase in lifespan compared to the OSK treatment, confirming that the benefits extended beyond anti-inflammatory effects.

Experiment 2: Wild-Type Mice

The next phase involved treating wild-type male mice at 18 months old (late-life stage). A single injection of the treatment resulted in:

• 12% increase in median lifespan.
• Preservation of body weight and improvements in physical activity.

Not a Senolytic: Effects on Senescent Cells

Contrary to senolytic therapies that eliminate senescent cells, the OSK treatment rejuvenates these cells without killing them. Eight months post-injection, the targeted cells remained viable, indicating that the therapy induces a healthier phenotype in senescent cells rather than removing them.

Implications for Anti-Aging and Safety

The OSK treatment was not associated with increased tumor formation, addressing a major concern with cellular reprogramming. Moreover, the therapy downregulated pro-inflammatory genes without inducing cell death, similar to the mechanisms of other geroprotective interventions like metformin and rapamycin.

The findings suggest that targeting a small population of stressed cells can improve organismal health by enhancing the body’s molecular buffering capacity against stressors. Further research into target organs and cell types could enable a more precise approach to rejuvenation and disease reversal.

References

1. Sahu, S. K., Reddy, P., Lu, J., Shao, Y., Wang, C., Tsuji, M., … & Belmonte, J. C. I. (2024). Targeted partial reprogramming of age-associated cell states improves markers of health in mouse models of aging. Science Translational Medicine, 16(764), eadg1777.
2. Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., … & Belmonte, J. C. I. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.
3. Lu, Y., Brommer, B., Tian, X., Krishnan, A., Meer, M., Wang, C., … & Sinclair, D. A. (2020). Reprogramming to recover youthful epigenetic information and restore vision. Nature, 588(7836), 124-129.