Title: Antibody therapies to remove proteins damaged by aging

Epigenetic reprogramming has captured a lot of attention in the longevity industry in the past decade. Some scientists think it's the holy grail that will largely solve aging. While I am a strong supporter of epigenetic rejuvenation therapies as treatments for aging, I'm not as optimistic about their effectiveness. My reasoning, in short, is that there are many things that epigenetic reprogramming will not be able to fix, no matter how advanced the reprogramming. A major reason for this is that the body is not made up of only cells. It's also made up of extracellular matrix (ECM) that surrounds those cells.

The ECM gets damaged in a stochastic time-dependent manner, and this contributes to aging of the body. I think this kind of damage will be hard to fix with rejuvenation technologies, partly because the body is simply not equipped with the repair machinery to fix all these types of damages, so even if you were to reprogram the machinery with epigenetic reprogramming, there is a lot of damage that just cannot be fixed by doing so. Other methods of repair are needed for these types of damages.

There are several types of stochastic damages that accumulate in the ECM with aging. Notable examples are isomerization, racemization, and glycation of proteins. There are no good treatments that can reverse or remove these types of damages in vivo, and I haven’t seen anything promising on the horizon for this for decades. A recent paper published in 2023 gives possible hope. (1) It describes a way to remove a type of isomerization damage in vivo.

In the paper, the authors targeted a specific type of age-related protein damage that is stochastic in nature. The damage they targeted was a change in a short amino acid sequence resulting in isoaspartate modification of the proteins. Such modifications can disrupt the normal function of the proteins. This kind of damage accumulates slowly with aging in humans and other animals. (2) Fortunately, the cells in the body produce an enzyme called L-isoaspartyl methyltransferase (PIMT) that is capable of repairing this isoaspartate modification. However, this enzyme is only produced inside of cells and, therefore, is unlikely to be able to fix significant amounts of damage outside of the cells. That is a major reason this damage accumulates with aging.

The authors injected the mice with a monoclonal antibody therapy that specifically targets the isoaspartate-damaged proteins. Once targeted, immune cells are signalled to remove the proteins with phagocytosis. When given to mice that have a short lifespan because they have a mutation that causes a loss of the PIMT enzyme, it resulted in a marked reduction in isoaspartate-damaged proteins in their brains and livers, a large reduction in inflammation in their bodies, and an improvement in cognitive function. It also doubled their lifespan. It's important to mention that they still lived much shorter than normal mice do.

When the same antibody therapy was given to old normal C57BL/6 mice, it was found to reduce the amount of isoaspartate-damaged proteins in their brains and livers and to restore various inflammatory cytokine levels in their plasma to levels similar to those found in young normal mice of the same strain. Unfortunately, the lifespan of the normal mice was not tested, but such an experiment would have taken considerably longer.

There are many questions to be answered about this study and similar kinds of therapies. What proportion of isoaspartate-damaged proteins that were removed with the therapy were intracellular versus extracellular? Does removing the proteins by phagocytosis, instead of repairing them, come with some yet unknown side effects? Regardless, I think these results are very interesting and potentially promising. I think this area certainly deserves much more attention, and I hope larger studies on the use of monoclonal antibody therapies targeting this isoaspartate damage as well as more types of stochastic protein damages will be done. Hopefully, some lifespan studies in normal mice will be conducted on such therapies in the near future.

References

1. Kalailingam P, Mohd-Kahliab KH, Ngan SC, Iyappan R, Melekh E, Lu T, Zien GW, Sharma B, Guo T, MacNeil AJ, MacPherson RE, Tsiani EL, O'Leary DD, Lim KL, Su IH, Gao YG, Richards AM, Kalaria RN, Chen CP, McCarthy NE, Sze SK. Immunotherapy targeting isoDGR-protein damage extends lifespan in a mouse model of protein deamidation. EMBO Mol Med. 2023 Dec 7;15(12):e18526. doi: 10.15252/emmm.202318526. Epub 2023 Nov 16. PMID: 37971164; PMCID: PMC10701600.
2.Fujii N, Takata T, Fujii N. Quantitative analysis of isomeric (l-α-, l-β-, D-α-, D-β-) aspartyl residues in proteins from elderly donors. J Pharm Biomed Anal. 2015 Dec 10;116:25-33. doi: 10.1016/j.jpba.2015.04.029. Epub 2015 May 5. PMID: 25983190.

Disclaimer
Although I have a BS degree in nutrition, have done intensive self-study on life-extension since 2003, and have worked in the field doing literature research since 2011, I am not a medical doctor or a licensed practitioner. Any information provided in this article is based on my personal research, opinions, and experiences. It is up to the reader to make their own decisions about what information to trust and which actions to take. I do not accept responsibility for any actions taken based on the information provided in this article.