Information theory of aging
According to The Information Theory of Aging, information loss from cells is a cause of the aging process.[1]. In cells, there are two main types of information, the genome, which is stored digitally as the four bases of DNA, A, C, T, and G, and the epigenome, the reader of the genetic information, which is stored in a digital-analog format as a three-dimensional DNA structures called chromatin[2]. Because the epigenome is partially analog, it is more susceptible than the genome to the introduction of informational noise. The theory was first proposed by David A. Sinclair, a biologist at Harvard Medical School who began studying aging in yeast in the 1990s with Lenny Guarente at MIT[3][4] and popularized in Lifespan: Why We Age and Why We Don't Have To, written by Sinclair and Matthew LaPlante (Atria Books/Simon & Schuster, 2019).[2]
The ITOA encompasses the idea that DNA breaks accelerates epigenetic information loss[5] and that there is a back-up copy of youthful information in each cell, which can be used to reset a cell's age, in the same way a scratched compact disc can be polished or a computer can have new software reinstalled[1][2]. The process of resetting a cell's youthful information by introducing or overexpressing the Yamanaka transcription factors, which were originally discovered as a combination to make stem cells from adult cells, has been likened to the recovery of lost information over a noisy channel by contacting the Observer, outlined in Claude Shannon’s seminal work from 1948, A Mathematical Theory of Communication. The Yamanaka factors used to reprogram cells are Oct4, Sox2, Klf4, and sometimes c-Myc (OSKM), in a process called partial epigenetic reprogramming or cellular rejuvenation. Sinclair has proposed that epigenetic reprogramming is a normal biological process that allows tissues to regenerate after injury, inflammation, or aging[2].
The first successful experiment to test the effect of partial reprogramming cells in vivo was carried out by Juan-Carlos Belmonte, Alex Ocampo and colleagues at the Salk Institute in an “accelerated aging” disease mouse model of Hutchison-Gilford Syndrome carrying a mutation in the LMNA gene[6]. When the genetically integrated OSKM cassette was induced for more than a week, the mice either died due to liver and intestinal failure or developed teratomas with longer exposure. However, when OSKM was induced in a cyclic fashion for only two days a week, symptoms of the disease were alleviated in multiple organs and the mice lived 40% longer. Later it was discovered if OSKM is induced for two and half weeks early in life, the progeroid mice live 15% longer[7]
A parallel effort by the Sinclair lab at Harvard Medical School, aiming to understand whether the epigenome could be reset, was based on a system using only three of the Yamanaka factors, OSK, excluding c-Myc, an oncogene[8]. Overexpression of OSK in human neurons protected them from cell death and restored youthful gene expression patterns. Importantly, overexpression of OSK in the entire mouse for a year was completely safe. When expressed in old RGCs post-mitotic retinal ganglion cells (RGCs), transcription and DNA methylation signatures were restored to a more youthful state, allowing RGCs to regrow after damage and vision improvements in aged and glaucomatous mice[8]. This was the first example of rejuvenation in vivo that reset the transcriptome and DNA methylome, and did so without proliferation, toxicity, or risk of cancer.
In 2023, whole-body expression of OSK in two-year-old mice, using an AAV9-OSK system[8] to reverse aging, extended overall lifespan by 7% and the remaining lifespan of the mice by 109%[9]. In the same year, researchers from Harvard Medical School, including Bruce Ksander and David Sinclair reported that OSK-mediated reprogramming of green monkey retinas could restore vision in a model of eye trauma known as Non-AION or NAION.
See Also:
- Information theory (aging)
- Cellular senescence
- Hallmarks of aging
- Shinya Yamanaka and Yamanaka Factors
- Induced pluripotent stem cell
- Horvath/epigenetic clock
- Sirtuin enzymes, regulators of the epigenome
- Extrachromosomal rDNA circle, a cause of aging in yeast cells that led to the ITOA
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- ↑ 1.0 1.1 Yang, Jae-Hyun; Hayano, Motoshi; Griffin, Patrick T.; Amorim, João A.; Bonkowski, Michael S.; Apostolides, John K.; Salfati, Elias L.; Blanchette, Marco; Munding, Elizabeth M.; Bhakta, Mital; Chew, Yap Ching; Guo, Wei; Yang, Xiaojing; Maybury-Lewis, Sun; Tian, Xiao (January 2023). "Loss of epigenetic information as a cause of mammalian aging". Cell. 186 (2): 305–326.e27. doi:10.1016/j.cell.2022.12.027. PMC 10166133 Check
|pmc=value (help). PMID 36638792 Check|pmid=value (help). Unknown parameter|pmc-embargo-date=ignored (help) - ↑ 2.0 2.1 2.2 2.3 Sinclair, David A. (2019). Lifespan : why we age--and why we don't have to. Matthew D. LaPlante, Catherine Delphia (First Atria Books hardcover ed.). New York. ISBN 978-1-5011-9197-8. OCLC 1088652276. Search this book on
- ↑ Johnson, F.Brad; Sinclair, David A; Guarente, Leonard (January 1999). "Molecular Biology of Aging". Cell. 96 (2): 291–302. doi:10.1016/s0092-8674(00)80567-x. ISSN 0092-8674. PMID 9988222. Unknown parameter
|s2cid=ignored (help) - ↑ Sinclair, David A; Guarente, Leonard (December 1997). "Extrachromosomal rDNA Circles— A Cause of Aging in Yeast". Cell. 91 (7): 1033–1042. doi:10.1016/S0092-8674(00)80493-6. PMID 9428525. Unknown parameter
|s2cid=ignored (help) - ↑ Oberdoerffer, Philipp; Michan, Shaday; McVay, Michael; Mostoslavsky, Raul; Vann, James; Park, Sang-Kyu; Hartlerode, Andrea; Stegmuller, Judith; Hafner, Angela; Loerch, Patrick; Wright, Sarah M.; Mills, Kevin D.; Bonni, Azad; Yankner, Bruce A.; Scully, Ralph (2008-11-28). "SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging". Cell. 135 (5): 907–918. doi:10.1016/j.cell.2008.10.025. ISSN 1097-4172. PMC 2853975. PMID 19041753.
- ↑ Ocampo, Alejandro; Reddy, Pradeep; Martinez-Redondo, Paloma; Platero-Luengo, Aida; Hatanaka, Fumiyuki; Hishida, Tomoaki; Li, Mo; Lam, David; Kurita, Masakazu; Beyret, Ergin; Araoka, Toshikazu; Vazquez-Ferrer, Eric; Donoso, David; Roman, Jose Luis; Xu, Jinna (2016-12-15). "In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming". Cell. 167 (7): 1719–1733.e12. doi:10.1016/j.cell.2016.11.052. ISSN 1097-4172. PMC 5679279. PMID 27984723.
- ↑ Milhavet, Ollivier; Lemaitre, Jean-Marc (2022-12-26). "Single short reprogramming early in life increases healthspan". Aging. 14 (24): 9779–9781. doi:10.18632/aging.204457. ISSN 1945-4589. PMC 9831720 Check
|pmc=value (help). PMID 36585922 Check|pmid=value (help). - ↑ 8.0 8.1 8.2 Lu, Yuancheng; Brommer, Benedikt; Tian, Xiao; Krishnan, Anitha; Meer, Margarita; Wang, Chen; Vera, Daniel L.; Zeng, Qiurui; Yu, Doudou; Bonkowski, Michael S.; Yang, Jae-Hyun; Zhou, Songlin; Hoffmann, Emma M.; Karg, Margarete M.; Schultz, Michael B. (December 2020). "Reprogramming to recover youthful epigenetic information and restore vision". Nature. 588 (7836): 124–129. Bibcode:2020Natur.588..124L. doi:10.1038/s41586-020-2975-4. ISSN 1476-4687. PMC 7752134 Check
|pmc=value (help). PMID 33268865 Check|pmid=value (help). - ↑ Macip, Carolina Cano; Hasan, Rokib; Hoznek, Victoria; Kim, Jihyun; Metzger, Louis E.; Sethna, Saumil; Davidsohn, Noah (2023-01-05). "Gene Therapy Mediated Partial Reprogramming Extends Lifespan and Reverses Age-Related Changes in Aged Mice". doi:10.1101/2023.01.04.522507. Unknown parameter
|s2cid=ignored (help)
