Blood Factors Reverse Epigenetic Age by Half in Rats

Researchers have demonstrated that epigenetic age can be halved in rats by using signals commonly found in the blood.

Epigenetic changes

One of the proposed reasons we age are the changes to gene expression that our cells experience as we get older; these are commonly called epigenetic alterations. These alterations harm the fundamental functions of our cells and can increase the risk of cancer and other age-related diseases.

Gene expression is modified by the addition of epigenetic markers to the DNA, which change the pattern of gene expression in a cell, suppressing or enhancing the expression of certain genes in a cell as the situation demands.

You might think of DNA as the building blocks and epigenetics as the instruction manual that explains how to assemble those blocks in order to make a certain structure to suit a particular situation.

This is how a cell in the liver knows that it needs to be a liver cell: the epigenetic instructions make sure that it is given the right guidance to become the correct cell type. At a basic level, these epigenetic instructions make sure that the genes needed to develop into a liver cell are turned on while the instructions specific to other types of cells are turned off.

However, as we age, our cells are exposed to damage from environmental factors and are subject to negative genomic changes through epigenetic mechanisms. Such changes accumulate over time and have been correlated with the decline observed in aging cells.

Epigenetic alterations in aging include changes to methylation patterns, and, in general, these correlate with a decrease in the amount of heterochromatin and an increase in chromosome fragility and transcriptional alterations (variance in gene expression), remodeling of chromatin (a DNA support structure that assists or impedes its transcription), and transcriptional noise.

Some researchers believe that these harmful epigenetic alterations could be reset to youthful levels in humans and, in doing so, reverse some aspects of aging, particularly improving the repair and rejuvenation of tissues and organs. There are a number of potential ways we might achieve this; today, we are going to focus on resetting the epigenetic age of cells using the signal molecules in our blood.

The internet of the body

Like the internet, the bloodstream is an information superhighway; it transmits signals between cells across huge distances, allowing remote parts of the body to communicate and regulate their activities. This network of blood vessels delivers nutrients, oxygen, and various kinds of cellular signals around the body to cells, so it is highly likely that it is a principal regulator of aging on a systemic level.

Researchers such as Dr. Dongsheng Cai have long proposed that certain elements of aging are controlled by the hypothalamus, a small area of the brain located at the base of the brain near the pituitary gland. While it’s very small, the hypothalamus plays a crucial role in many important functions, including releasing hormones and regulating body temperature. Dr. Cai and his team have discovered evidence that specialized stem cells living in the hypothalamus regulate systemic aging via secreted miRNAs [1].

As we age, these specialized cells die off and the hypothalamus becomes increasingly dysfunctional and unable to properly control the various functions it once did, in this manner, stem cell exhaustion in the hypothalamus seems to accelerate aging. This then leads to it secreting signals that are either not enough or too much, depending on the type. This then contributes to the shift in the environment of the bloodstream, as do other sources of harmful signaling, such as senescent cell secretions, changing it to a pro-aging rather than pro-youthful environment.

As we get older, there is typically a build-up of pro-inflammatory signals known as cytokines, which in low levels are helpful in healing and regeneration but when present in excessive amounts harm tissue upkeep and repair by blocking stem cell activity, cause immune cells to become dysfunctional, and contribute to a rise in systemic inflammation levels that support the onset of various age-related diseases. Typical cytokines that increase in concentration in the blood as we age are transforming growth factor beta 1 (TGF-ß1), interleukin 6 (IL6), and tumour necrosis factor alpha (TNFa).

Resetting epigenetic age with blood factors

Drs. Irina and Michael Conboy have long suggested with their research that certain elements of aging and tissue rejuvenation can be spurred by the calibration of signaling molecules in the blood. Indeed, their experiments have shown that youthful tissue function can be restored in aged mice by selectively reducing the level of key cytokines in the blood [2]. Doing so has the result of releasing stem cells, normally blocked from working by inflammatory signals typically present in old age, and allowing them to resume their activity. This return to activity allows the stem cells to begin repairing tissue and creating replacement cells as they do when the host is young.

Other researchers, such as Dr. Amy Wagers, Dr. Tony Wyss-Coray, and Dr. Hanadie Yousef, have also conducted research that strongly supports the idea that the epigenetic element of aging might at least be partially reset to a youthful level by calibrating, removing, or adding various signaling factors in blood.

While there are likely hundreds of factors in blood that may play a role in aging, the evidence is increasingly supporting the idea that a handful of key factors sit at the top of the process and regulate the hundreds of factors below. In other words, targeting these key factors may reverse epigenetic aging and restore youthful tissue function in aged individuals.

The results from a new study in rats suggest once again that the rejuvenation of aged organs and tissues is possible by resetting the epigenetic state of old cells back to a more youthful one using blood factors. It should be noted at this point that the results have been published as a preprint on bioRxiv, a site on which authors are able to make their research immediately available to the scientific community and receive feedback from their colleagues before they are submitted to journals for peer review and publication. With that caveat out of the way, let’s take a look at the data.

The researchers delivered Elixir, an undisclosed mixture of plasma fractions presumably isolated from young rat plasma, to aged rats. They state that their technique is based on heterochronic parabiosis but forgoes the need to physically join an old and young animal together so that they share circulatory systems.

The researchers claim that their results are averaged based on measurements taken using multiple epigenetic clocks.

Crucially, plasma treatment of the old rats reduced the epigenetic ages of blood, liver and heart by a very large and significant margin, to levels that are comparable with the young rats. According to the six epigenetic clocks, the plasma fraction treatment rejuvenated liver by 73.4%, blood by 52%, heart by 52%, and hypothalamus by 11%. The rejuvenation effects are even more pronounced if we use the final versions of our epigenetic clocks: liver 75%, blood 66%, heart 57%, hypothalamus 19%. According to the final version of the epigenetic clocks, the average rejuvenation across four tissues was 54.2%.

If these results are correct, then the epigenetic age of these rats has essentially been halved and returned to a level seen in young rats. On top of these epigenetic clock measurements, a number of other aging biomarkers saw improvement:

• Pro-inflammatory cytokines IL-6 and TNFa were reset to a lower, more youthful, level
• Blood triglycerides were reduced to a youthful level
• HDL cholesterol were increased to a youthful level
• Blood glucose levels dropped to more youthful levels
• Cognition became more youthful according to tests in a Barnes Maze
• Glutathione (GSH), superoxide dismutase (SOD), and some other antioxidant levels were reset to more youthful levels

Unanswered questions

These impressive results were apparently achieved with just four injections; however, it remains to be seen if these changes are persistent and for how long.

Given that there are many feedback loops in the system; it could be the case that once reset, the changes will persist for considerable time; after all, it takes decades for your system to break down and reach the point where aging becomes apparent.

There is also the question with blood factor-based rejuvenation experiments as to if it is what you put into aged blood or what you take out that is key to rejuvenation.

The Conboys have, in the past, suggested that reducing the excessive levels of proinflammatory cytokines in aged blood is likely more critical than adding anything found in young blood. In other words, it’s more about calibration of aged blood and the cytokines therein rather than there being any “special sauce” in young blood that spurs rejuvenation.

Of course, if could just as easily be both, and the past results of the Conboys, which showed that reduced levels of TGF-ß1 resulted in tissue rejuvenation, support this notion. Equally, there have been other experiments by researchers such as Dr. Amy Wagers and Dr. Tony Wyss-Coray in which factors found in young blood were added to aged blood and nothing was removed, which also spurred some level of rejuvenation.

In this particular experiment, the researchers only added replacement young blood plasma factors without removing anything, which suggests that what they did was enough to have a significant effect. It does appear in this case that whatever was added was able to encourage some level of rejuvenation in the context of epigenetic age. This could be more effective than the calibration and removal of harmful cytokines via filtering as proposed by the Conboys.

It could be that adding enough key factors is enough to spur rejuvenation without the need to carefully calibrate factors in aged blood. That remains to be seen, and at this early stage, it is too soon to say if what you take out is more important than what you put in or even if doing both will produce an even better result.

Conclusion

What needs to happen next is a lifespan study to see if resetting epigenetic age in this manner leads to an increase in healthy lifespan in rats. Also, this experiment used a small number of rats, so a greater number of rats used in such a follow-up lifespan study would be ideal. It would also be interesting to see if these results can be replicated in mice as a step towards moving this to human trials.

Taken as a whole, these results and similarly focused studies further support that methylation patterns in nuclear DNA are not merely the hands of a clock indicating cellular age but are also the workings of that clock. This is further evidence that epigenetic aging is one of the primary reasons we age and that its reversal could have big ramifications for human aging and healthy longevity if successfully translated.

Literature

[1] Zhang, Y., Kim, M. S., Jia, B., Yan, J., Zuniga-Hertz, J. P., Han, C., & Cai, D. (2017). Hypothalamic stem cells control ageing speed partly through exosomal miRNAs. Nature, 548(7665), 52-57.

[2] Yousef, H., Conboy, M. J., Morgenthaler, A., Schlesinger, C., Bugaj, L., Paliwal, P., … & Schaffer, D. (2015). Systemic attenuation of the TGF-ß pathway by a single drug simultaneously rejuvenates hippocampal neurogenesis and myogenesis in the same old mammal. Oncotarget, 6(14), 11959.