Tomorrow Bio

The reasons why people decide to sign up for cryonics, aka human cryopreservation, are varied. From living a bit longer than is currently possible to traveling between galaxies, the opportunities offered by the possible success of this technology are endless. The future world will likely be similar in some ways, and very different in others, from the one we live in now. It’s hard to predict what members of Tomorrow Bio, the fastest-growing cryonics organization in Europe, will encounter if they wake up from cryopreservation. Yet, one thing is certain. If and when revival is possible, it means that medical technology will have advanced enough to cure aging.

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Wondering how we will get there? Senotherapeutics, and more specifically senolytics and senomorphics drugs, might be (one of) the answers.

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Understanding Aging

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You might ask yourself: how come we are still so far from being able to treat the effects of old age on the human body? The truth is that so-called “aging” is a complex set of interconnected processes, which we still don’t know everything about. Just think about it, it was only recently that the 9 hallmarks of aging were discovered and classified. Since then, various researchers have been investigating how to tackle one or more of these phenomena. Senotherapeutics focus specifically on one of these processes called cellular senescence.

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What Is Cellular Senescence?

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Cellular senescence is a state that can occur in all cells within a body, perpetuated by many drivers and also in response to a variety of different stresses. Our body is subject to harmful stimuli all the time and precise conditions are required for the cell to become senescent, (aka old). In fact, depending on cell types, and on the intensity and nature of the stress, cells can respond by inducing repair, death or senescence.

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Some processes that can produce senescence are:

DNA damage
Replicative stress (shortening of telomeres)
Mitochondrial dysfunction
Inflammation
Oxidative stress
Oncogene activation

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When a cell becomes senescent, there are two main consequences. First, their cell-cycle stops permanently. This means that the cells are incapable of dividing anymore. On top of that, they start secreting a variety of different markers, known as the Senescence Associated Secretory Phenotype (SASP).

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Senescence and Age-Related Diseases

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That said, cellular senescence is not always detrimental to the body.

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Let’s take a look at one of the most infamous examples, which concerns the development and treatment of tumors. One of the primary goals of anti-cancer therapies is limiting the unrestrained proliferation of cancerogenous cells. Senescence may come into play here, as its cell-cycle arresting effect can be used as a tumor suppressor mechanism. Since they can no longer divide, they can’t proliferate. Senescence can suppress tumorigenesis not only by limiting the malignant transformation of pre-neoplastic cells but also by halting the proliferation of tumor cells. [1]

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On the other hand, the secretion of the SASP markers create an inflammatory immunosuppressive microenvironment which is favorable for tumor growth. Taking all this into account, approaches that harness the growth inhibitory effects of senescence while limiting its detrimental effects are likely to have great clinical potential. [1]

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Now, what other diseases are fostered by the presence of senescent cells (SC) in the human body? Chronic inflammation caused by SASP could be driving the aging process, along with other age-related diseases such as: osteoporosis, frailty, cardiovascular diseases, osteoarthritis, pulmonary fibrosis, renal diseases, neurodegenerative diseases, hepatic steatosis, and metabolic dysfunction. [2]

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Finally, senescence of stem cells can limit the tissue regenerative potential.

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old man with wrinkles — Cellular senescence can cause much more than just wrinkles

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A Possible Solution: Senotherapeutics

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The term “senotherapeutics'' refers to therapeutic strategies developed to specifically target cellular senescence. While this is a relatively new field of study, it didn’t take long for research to move into clinical trials. Investments and anticipation about the possible results of these therapies are high. As stated in the paper Senotherapeutics for healthy ageing by LJ Niedernhofer (2018): the development of drugs that specifically kill senescent cells is envisioned to have significant therapeutic effects on slowing ageing phenotypes, treating age-related comorbidities and improving resiliency. [3]

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The two main branches of senotherapeutics are senolytics and senomorphics.

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Senolytics

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Senolytics are pharmacological agents (drugs) that selectively kill senescent cells (SC) without the need of genetic engineering. They are able to recognize senescence and act on it, while leaving all other healthy cells unaffected. How can they achieve that?

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Frequently, SC have a high expression of genes that repress apoptosis, which is the process of programmed cell death. This is how they can stop the cell-cycle and not die. By inhibiting these anti-apoptosis proteins, senolytics drive senescence cells to programmed death. Since these proteins are present only under senescence, healthy cells remain undisturbed. At least, that is what we assume happens.

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One challenge in dealing with SC is that there are several different populations of them in our tissues and organs. Each of them uses its specific pro-survival pathways, which prevent them from dying. Medical technology will probably need to develop and administrate multiple senolytic drugs to remove senescence.

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A remarkable result obtained with the administration of senolytics dasatinib and quercetin in patients with diabetic kidney disease and idiopathic pulmonary disease have proven to be effective in reducing the expression of the selected biomarker for senescence, p16(Ink4a). The data obtained during the clinical trials indicate that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan. [4]

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Senomorphics

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There is another possible way of increasing longevity and life span by targeting senescence. While senolytics work on killing SC, their cousin senomorphics target only their detrimental aspects. They work on reducing and limiting the inflammatory effect caused by the secretion of SASP. Senescent cells won’t die but they will possibly stop harming the body.

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To achieve this, senomorphics inhibit the protein in the cell that drives the expression of the SASP components. Two examples of these pharmacological agents are metformin and rapamycin, the former approved for type 2 diabetes, and the latter for immunosuppression.

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So, What Is More Beneficial?

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There are three main reasons to believe that senolytic drugs have more promising effects than senomorphic drugs.

To begin with, by killing SC, senolytics can be administered only when needed. In contrast, senomorphic components should be taken constantly, to keep the inflammatory effect of these cells at bay.
Secondly, senolytics prevent the chance of senescent bypass. SC can in fact escape their condition through mutation, which in most cases is malignant causing tumorigenesis.
Finally, there is still no clear evidence that reducing the SASP production would positively impact longevity and age-related diseases.

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Interesting to note that some compounds, for example fisetin, have senomorphic effects on some cell types while having senolytic activity on others. There is still much research needed to define which components act on which age-related processes. These drugs may enhance healthspan and delay, prevent, or treat multiple chronic diseases, and age-related declines. However, this is not a certainty yet. Finally, we do not yet know what the long-term consequences of using senotherapeutics will be.

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people running — Calorie restriction, fasting, and exercise have an impact on SC reduction - but we don’t know to what extent

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Life After Revival

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If you are signed up for cryonics, or you’re considering it, there's a good chance you are also interested in human longevity. Extending life has always been one of the goals of medical science. Nowadays, many people are trying to lengthen their lifespan and healthspan with diets, exercises, good habits and whatnot. Meanwhile, scientific research is making great strides in discovering the mechanisms of old age and how to counteract them.

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However, we cannot predict whether the solution will be found in the coming decades. It may take a long time before medical technology will advance enough to treat age-related diseases that are today the main causes of death. For this reason, many people have decided to rely on cryonics.

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Cryonics aka Human Cryopreservation

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Human cryopreservation is an advanced medical procedure that, through the use of cryogenic temperatures, pauses all biological processes within a body after legal death. This way, the process of death is interrupted. At the end of the procedure, the patient is in a state of vitrification and stored at -196°C which can be maintained indefinitely. At Tomorrow Bio, the first cryonics organization in Europe, we offer all-inclusive cryopreservation plans.

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By preserving the body, we have a chance of reaching a future where old age will hopefully be little more than a memory. A future society where new drugs and treatments will be able to cure diseases untreatable today. There, a cancer diagnosis won’t be a death sentence, as is unfortunately often the case nowadays.

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Clearly, we can’t tell how long it may take before we get there. A groundbreaking discovery can revolutionize the medical field in a short time, but researchers may need decades or even centuries to reach that discovery. As there is no time limit for cryopreservation, our patients can remain safely stored in their cryogenic storage dewar for as long as it takes.

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Future medical technology that is unimaginable today, may eventually reverse the procedure and revive cryonics patients.

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Conclusion

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For many, cryopreservation is a sort of a bet for life extension. So are senotherapeutics. With the necessary monetary investment, research may advance enough to tell us clearly whether these are the drugs and treatments we are waiting for. Do we have the solution to aging and the key to life extension? For now we can’t say, but exciting times lie ahead.

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And what do you expect from the future? If you like to discuss these topics, take a look at our online editorial Tomorrow Insight. You can also join our Discord server, where we discuss cryonics, technology and futurism on a daily basis. Finally, if you want to learn more about human cryopreservation, download our short ebook below!

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