Aging and eye disease

2021-10-19T10:08:12Z

LindsayC: New article draft

Most visual impairments uncorrectable by glasses are age-related; primary conditions in being cataract, glaucoma, macular degeneration, and diabetic retinopathy. A recent study confirms visual impairment in the US increases as a function of age and is more prevalent than previous accounts. Additionally, large economic costs are incurred as a result of age-related disease.

=== Cataract ===

=== Glaucoma ===

=== Macular Degeneration ===

=== Diabetic Retinopathy ===
{{ Draft-article }}

2021-09-09T15:35:01Z

LindsayC: Updated formating to include contents

=== 1. Epigenetics ===
Epigenetics simply refers to heritable yet modifiable features or marks on the genome which contribute to gene expression. These features impact the chromatin structure without any change in the nucleotide sequence of DNA and function to regulate how genes are transcribed into proteins.<ref name=":0">Moosavi, A., & Ardekani, A. M. (2016). Role of epigenetics in biology and human diseases. In ''Iranian Biomedical Journal'' (Vol. 20, Issue 5, pp. 246–258). Pasteur Institute of Iran. <nowiki>https://doi.org/10.22045/ibj.2016.01</nowiki></ref><ref name=":1">''Genetics, Epigenetic Mechanism - StatPearls - NCBI Bookshelf''. (n.d.). Retrieved September 8, 2021, from <nowiki>https://www.ncbi.nlm.nih.gov/books/NBK532999/?report=classic</nowiki></ref> The most prominent and well-studied of these epigenetic features is DNA methylation.<ref>Reik, W., Dean, W., & Walter, J. (2001). Epigenetic reprogramming in mammalian development. In ''Science'' (Vol. 293, Issue 5532, pp. 1089–1093). American Association for the Advancement of Science. <nowiki>https://doi.org/10.1126/science.1063443</nowiki></ref><ref>Li, Y. (2021). Modern epigenetics methods in biological research. ''Methods'', ''187'', 104–113. <nowiki>https://doi.org/10.1016/J.YMETH.2020.06.022</nowiki></ref> Measurements of DNA methylation patterns have also been used to form the basis for [[Epigenetic clock|epigenetic aging clocks]], as a potential measure of biological age across the mammalian kingdom.<ref>Horvath, S. (2013). DNA methylation age of human tissues and cell types. ''Genome Biology'', ''14''(10). <nowiki>https://doi.org/10.1186/gb-2013-14-10-r115</nowiki></ref> Other common marks include histone modification, chromatin structure and microRNA (miRNA) or non-coding RNA (nc-RNA).<ref name=":1" />

=== 2. Epigenetic Reprogramming ===
Epigenetic reprogramming refers to a significant remodeling of the epigenetic features or methylation patterns of the genome. Historically the term has referred to such changes occurring in the context of early organismal development. It has also been studied in relation to cancer and other disease states.<ref name=":0" /><ref>Feinberg, A. P. (2018). The Key Role of Epigenetics in Human Disease Prevention and Mitigation. ''<nowiki>Https://Doi.Org/10.1056/NEJMra1402513</nowiki>'', ''378''(14), 1323–1334. <nowiki>https://doi.org/10.1056/NEJMRA1402513</nowiki></ref> Within the context of longevity research, the term has more specifically been used to refer to a new strategy for cellular rejuvenation.<ref name=":2">Roux, A., Zhang, C., Paw, J., Zavala-Solorio, J., Vijay, T., Kolumam, G., Kenyon, C., & Kimmel, J. C. (2021). Partial reprogramming restores youthful gene expression through transient suppression of cell identity. ''BioRxiv'', 2021.05.21.444556.</ref><ref name=":3">Lu, Y., Brommer, B., Tian, X., Krishnan, A., Meer, M., Wang, C., Vera, D. L., Zeng, Q., Yu, D., Bonkowski, M. S., Yang, J. H., Zhou, S., Hoffmann, E. M., Karg, M. M., Schultz, M. B., Kane, A. E., Davidsohn, N., Korobkina, E., Chwalek, K., … Sinclair, D. A. (2020). Reprogramming to recover youthful epigenetic information and restore vision. ''Nature'', ''588''(7836), 124–129. <nowiki>https://doi.org/10.1038/s41586-020-2975-4</nowiki></ref>

==== 2.1 In Development ====
Two major reprogramming events are known to occur in early development of mammals, in germ cells and early embryos. During these events, methylation patterns are reprogrammed genome wide.<ref>Lepikhov, K., Arand, J., Wossidlo, M., & Walter, J. (2012). Epigenetic Reprogramming in Mammalian Development. In ''Encyclopedia of Molecular Cell Biology and Molecular Medicine''. <nowiki>https://doi.org/10.1002/3527600906.mcb.201100038</nowiki></ref><ref>Kerepesi, C., Zhang, B., Lee, S.-G., Trapp, A., & Gladyshev, V. N. (2021). Epigenetic clocks reveal a rejuvenation event during embryogenesis followed by aging. ''Sci. Adv'', ''7'', 6082–6107. <nowiki>http://advances.sciencemag.org/</nowiki></ref>

==== 2.2 In Cancer ====
All cancer cells are known to demonstrate epigenetic changes.<ref name=":4">Baylin, S. B., & Jones, P. A. (2016). Epigenetic determinants of cancer. ''Cold Spring Harbor Perspectives in Biology'', ''8''(9). <nowiki>https://doi.org/10.1101/cshperspect.a019505</nowiki></ref> These changes lead to induced pluripotency, the transformation of a differentiated cells into a stem cells, resulting in cancer stem cells.<ref name=":4" /><ref>Suvà, M. L., Riggi, N., & Bernstein, B. E. (2013). Epigenetic reprogramming in cancer. In ''Science'' (Vol. 340, Issue 6127, pp. 1567–1570). American Association for the Advancement of Science. <nowiki>https://doi.org/10.1126/science.1230184</nowiki></ref> Transcription factors initiate DNA transcription and are known to work synergistically with epigenomic regulators in the promotion of cancer.<ref>Wilson S, Filipp FV. A network of epigenomic and transcriptional cooperation encompassing an epigenomic master regulator in cancer. ''npj Systems Biology and Applications''. 2018;4(1):24. doi:10.1038/s41540-018-0061-4</ref> Modification of aberrant epigenetic marks has been proposed as a strategy for fighting cancer by utilizing solely epi-drugs or in combination with chemotherapy or immunotherapy.<ref>Lu, Yuanjun, Chan, Y.-T., Tan, H.-Y., Li, S., Wang, N., & Feng, Y. (2020). Epigenetic regulation in human cancer: the potential role of epi-drug in cancer therapy. ''Molecular Cancer 2020 19:1'', ''19''(1), 1–16. <nowiki>https://doi.org/10.1186/S12943-020-01197-3</nowiki></ref>

==== 2.3 As a Rejuvenation Strategy ====
Applying epigenetic reprogramming in ''naturally aged'' mice has more recently been shown to improve memory/cognition, promote muscle regeneration, and restore vision.<ref name=":3" /><ref>Wang, C., Ros, R. R., Martinez-Redondo, P., Ma, Z., Shi, L., Xue, Y., ... & Belmonte, J. C. I. (2021). In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche. ''Nature Communications'', ''12''(1), 1-15.</ref><ref>Rodríguez-Matellán, A., Alcazar, N., Hernández, F., Serrano, M., & Ávila, J. (2020). In Vivo Reprogramming Ameliorates Aging Features in Dentate Gyrus Cells and Improves Memory in Mice. ''Stem cell reports'', ''15''(5), 1056-1066.</ref> Analyses using epigenetic aging clocks, which measure some aspects of biological age, show that cellular reprogramming resets epigenetic age.<ref>Ocampo, A., Reddy, P., & Belmonte, J. C. I. (2016). Anti-aging strategies based on cellular reprogramming. ''Trends in molecular medicine'', ''22''(8), 725-738.</ref>

It has been envisioned by some scientists as a therapy that could be used periodically, perhaps every few decades, to continually reverse aging in humans.

===== 2.3.1 Information theory of aging =====
David Sinclair of Harvard Medical School has theorized that progressive changes to the epigenome occur with age and result in a loss of information or mistakes which lead to aging. He uses the analogy of a compact disc with scratches that can be polished off to recover function. Similarly, he believes the epigenome can be recovered to its youthful state.<ref>''Lifespan: Why We Age―and Why We Don’t Have To: Sinclair PhD, David A., LaPlante, Matthew D.: 9781501191978: Amazon.com: Books''. (n.d.). Retrieved June 30, 2021, from <nowiki>https://www.amazon.com/Lifespan-Why-Age_and-Dont-Have/dp/1501191977/ref=asc_df_1501191977/?tag=hyprod-20&linkCode=df0&hvadid=366299527575&hvpos=&hvnetw=g&hvrand=14568336801310889272&hvpone=&hvptwo=&hvqmt=&hvdev=c&hvdvcmdl=&hvlocint=&hvlocphy=9007869&hvtargid=pla-700016961004&psc=1&tag=&ref=&adgrpid=79033899111&hvpone=&hvptwo=&hvadid=366299527575&hvpos=&hvnetw=g&hvrand=14568336801310889272&hvqmt=&hvdev=c&hvdvcmdl=&hvlocint=&hvlocphy=9007869&hvtargid=pla-700016961004</nowiki></ref> Further support of this theory placing the epigenetic changes at the center of aging will require more empirical evidence, particularly due to the novel nature of reprogramming research.

=== 3. Epigenetic Modification Strategies for Rejuvenation ===

==== 3.1 Yamanaka Factors ====
Epigenetic reprogramming for rejuvenation is based on work that earnt Shinya Yamanaka the 2012 Nobel Prize in Medicine. Yamanaka showed that it was possible to reprogram adult body cells back into biologically immortal pluripotent stem cells capable of turning into any cell of the body.<ref name=":17">Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. ''cell'', ''126''(4), 663-676.</ref><ref name=":5">Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., & Yamanaka, S. (2007). Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors. ''Cell'', ''131''(5), 861–872. <nowiki>https://doi.org/10.1016/j.cell.2007.11.019</nowiki></ref> These reprogrammed cells show profound reversion of cellular identity, accompanied by a ‘youthful’ embryonic epigenetic state, This was achieved by activating only four transcription factors - the ''Yamanaka factors'' - OCT4, SOX2, KLF4, and MYC (or OSKM).<ref name=":17" /><ref name=":5" /> These transcription factors cause epigenetic changes that alter gene expression, instead of making changes to DNA itself.<ref name=":17" /><ref name=":5" />

==== 3.2 Partial Reprogramming Using Yamanaka Factors ====
Scientists in the aging biology field have since expanded upon this work to show that a partial version of this epigenetic reprogramming technique may reverse multiple aspects of aging.<ref name=":6">Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., Li, M., Lam, D., Kurita, M., Beyret, E., Araoka, T., Vazquez-Ferrer, E., Donoso, D., Roman, J. L., Xu, J., Rodriguez Esteban, C., Nuñez, G., Nuñez Delicado, E., Campistol, J. M., … Izpisua Belmonte, J. C. (2016). In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming. ''Cell'', ''167''(7), 1719-1733.e12. <nowiki>https://doi.org/10.1016/j.cell.2016.11.052</nowiki></ref> Work from Juan Carlos Izpisua Belmonte's lab showed that it is possible to modify the reprogramming technique and achieve 'youthful' rejuvenation, without resetting a cell with a defined identity into a stem cell. This is known as partial reprogramming, and commonly referred to as epigenetic reprogramming. Epigenetic aging clocks, which measure the methylation status of various tissues and predict biological age, have been observed to be reset with partial cellular reprogramming.<ref>Olova, N., Simpson, D. J., Marioni, R. E., & Chandra, T. (2019). Partial reprogramming induces a steady decline in epigenetic age before loss of somatic identity. ''Aging Cell'', ''18''(1). <nowiki>https://doi.org/10.1111/acel.12877</nowiki></ref>

In vivo epigenetic reprogramming can lead to regeneration of the optic nerve and visual recovery in mouse models of optic nerve impairment due to injury, glaucoma, and natural aging.<ref name=":3" />

==== 3.3 Multipotent Transcription factors ====
Multipotent cells, which are cells that are not fully iPSCs yet still partially undifferentiated, have been investigated for reprogramming. This mitigates the risk of oncogenesis.<ref name=":2" />

Researchers from the Alphabet (Google) subsidiary, Calico, analyzed different combinations of Yamanaka factors on different cell types and found they restore youthful gene expression but also impact cell identity. Most importantly, they found any combination of factors had the potential to cause pluripotency. This means even transient reprogramming can be oncogenic with more transcription factors conferring higher risk. However, the suppression of cell identity and restoration of youthful gene expression may be decoupled, so that there may be yet to be discovered methods which restore youthful phenotype with low risk for pluripotency.<ref name=":2" />

=== 4. Methods for Introducing Reprogramming Factors ===

==== 4.1 Viral Vector ====
This technology has been delivered via adeno-associated viral vector (AAV) in a mouse model of glaucoma.<ref name=":3" /> The specific AAV applied, Tet-Off AAV2, uses tetracycline class drugs as an on-off switch to induce transcription for a controlled duration.

==== 4.2 Messanger RNA (mRNA) ====
In addition to using AAV technology to introduce transcription factors, mRNA technology can also be employed. Turn Biotechnology is an example of a company currently investigating mRNA-based technology for epigenetic reprograming.<ref>''Product — turn.bio''. (n.d.-b). Retrieved September 8, 2021, from <nowiki>https://www.turn.bio/product#pipeline-intro</nowiki></ref>

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[[Category:Longevity]]
[[Category:Pillar Articles]]