What is rejuvenation?

In the previous section we saw that ageing is a damage accumulation process, and that age-related diseases are the result of it. Now the question is, what kind of damage are we talking about, and what is science doing about it?

Traditional approaches

Let’s start from the second question. Until relatively recently, the only approaches to the problem have been only two: the geriatric approach and the gerontological approach.

Geriatrics deals with the consequences of the damage metabolism has caused, but not with the damage itself. Damage that has already been laid will stay right where it is, and since nothing prevents further damage from being laid and causing more problems, the situation will go from bad to worse. For example, if an elderly person suffers from high blood pressure, the way geriatrics will go about the problem is not that of fixing what causes pressure to grow high, but rather that of administering treatments (generally pills) that manage to lower the pressure. As these treatments work on the symptoms rather than the cause, patients must continue them forever; their effects would terminate if the treatments were interrupted. It is quite clear that trying to attack ageing in this way is like shovelling water (or rather, a waterfall) with a pitchfork.

On the other hand, gerontology focuses on prevention: The idea is that of tinkering with metabolism in order to prevent it from causing damage in the first place, or at least slow down the rate at with the damage is created. In principle, this is a fantastic idea, and if it worked, it would make for an effective cure against age-related diseases, but there is a problem. Our metabolism is far too complex to hope to be able to tweak it just enough to prevent it from causing damage without annoying side effects—like, uh, death.

Map of human metabolism
It looks like the map of Hyrule from The Legends of Zelda, but it is actually the map of human metabolism, taken from Medicalxpress.com.

The third option

A third approach was suggested at the turn of the millennium by Aubrey de Grey, a British biogerontologist who has dedicated his life to defeating ageing. Remember the messy room in the previous article? In that example, the equivalent of geriatrics would be trying to live with the chaos as best as you could, whereas a gerontological approach would be that of trying to use the room without ever messing it up even a little bit. Neither of these ideas is ever going to work, but there is a very simple way to prevent the room from becoming a mess: periodic maintenance. Well before the room becomes too dirty or untidy, you arm yourself with brooms, mops, detergents, and elbow grease and you give the room a good clean. The room will get back to its former splendour, and what’s more, the more often you clean it, the easier it will be to clean it. Furthermore, using the room will be more practical than if you cleaned it only rarely. The same is true of cars: There are classic cars that are a hundred years old, even though they were designed to last only maybe 15 years. The reason they still work is that somebody has done serious maintenance work on them.

As you probably figured out by now, the idea behind the third approach is that, just like you can clean up a room before it turns into Jumanji and you can repair a car before it exhales its last exhaust fume, you might be able to fix the human body before it is too late. Rather than focusing on the symptoms or trying to tinker with metabolism, we could let it do its thing and simply periodically fix the damage before it accumulates beyond a critical threshold. If it worked, we would be able to achieve the so-called negligible senescence. This is a feature of few animal species, whose members do not show any appreciable sign of ageing. Their health does not decline as a function of their age, they don’t experience any functional decline, their reproductive ability doesn’t change with time (yay!), and their probability of death doesn’t grow as they grow older. Lucky bastards, eh?

This approach, often called the ‘maintenance approach’, was introduced by de Grey as SENS, or Strategies for Engineered Negligible Senescence. The name comes from the fact that a patient who were to undergo SENS would not be ‘cured’ of the ageing process; ageing would continue as normal, but the damage it lays would be periodically fixed, effectively rejuvenating the patient. The patient senescence (i.e., ageing) would always be kept at negligible levels—ideally, around 25 years of age. In other words, one could be 90 chronologically, but 25 biologically. This is why we talk about rejuvenation (or rejuvenation therapies, or rejuvenation biotechnologies): Their effect would be to periodically rejuvenate the body. At the bottom of this page, you’ll find a little history of SENS and SENS Research Foundation; for now, let’s focus on the technical details.

We can now answer the first question we asked at the beginning of this article: What is the damage we have been talking about, and how does SENS, or more generally, the maintenance approach, plan to repair it?

The seven deadly things and how to fix them

SENS divides the damage into seven categories. These categories may contains different damage subtypes, but the good news is that the interventions needed to repair different subtypes are the same, differing from each other only in detail. The following is a layman’s introduction to the seven categories and the kind of interventions that SENS suggests to fix them.

>> Introduction to SENS on sens.org >> >> Introduction to SENS on Fight Aging! >>

MitoSENS: Obviating mitochondrial damage

Mitochondria are organelles located inside our cells. Their function is producing energy to power the cells themselves. For reasons beyond the scope of this article, mitochondria have their own DNA, different from that inside the nucleus of the cell.

Because of the constant free radical storm it is subject to, mitochondrial DNA undergoes mutations that affect the efficiency of mitochondria themselves; worse still, cells that are overcome with mutant mitochondria become toxic for others.

The solution to this problem might be the so-called allotopic expression—that is, ‘backing up’ mitochondrial genes inside the cell nucleus, which is much better protected against free radical attacks. This process may happen spontaneously as well (indeed, some mitochondrial genes migrated into the cell nucleus of their own accord during our evolution) and in 2016 SENS Research Foundation managed to achieve stable allotopic expression of two more mitochondrial genes in the lab.

>> MitoSENS on sens.org >> >> Mitochondrial mutations on Fight Aging! >>

LysoSENS: Eliminating intracellular junk

Lysosomes are another kind of organelles in the cell. Their function is to recycle byproducts created by the cell as it performs its functions. Unfortunately, not all byproducts are digestible by lysosomes, and the stuff lysosomes can’t digest will pile up, impairing its functioning. (It can even explode, which you can imagine how fun it will be for the cell.) In old age, this leads to a range of pathologies, among which for example macular degeneration and cardiovascular diseases.

To solve this problem, SENS proposes to ‘upgrade’ lysosomes through genetic engineering: with the right genes, it might be possible to make lysosomes able to produces special enzymes able to digest stuff that is indigestible at the moment. SENS did achieve some success in this department; this page lists articles on the subject.

>> LysoSENS on sens.org >> >> Lysosomal decline on Fight Aging! >>

AmyloSENS: Eliminating extracellular junk

Extra cellular junk is basically a bunch of misshapen proteins that accumulate between cells and stick to each other. The result of this process is a sticky web that ‘strangles’ cells and prevents tissues from working correctly. Most of these proteins are the so-called amyloids. Their piling up causes a range of age-related pathologies, including the ill-famed Alzheimer’s disease.

This problem could be solved through enhanced phagocytosis— i.e., using vaccination to train the immune system to recognise and eliminate extracellular junk.

>> AmyloSENS on sens.org >> >> Amyloids on Fight Aging! >>

RepleniSENS: Stem cells against cell loss and atrophy

Our cells are not immortal: Their life is limited, and it shortens more and more as they divide to reproduce. The reason we don’t fall apart because of cell shortage in a few years after birth is that we have a reservoir of so-called stem cells, which have no limitation to their ability to reproduce. The problem is, even though they can reproduce as much as they like and specialise into specific cell types, our stem cell pool eventually starts running out of cells. As a result, in old age our bodies suffer from cell loss in several tissues, leading to pathologies such as Parkinson’s disease and sarcopenia.

The solution SENS proposes for this problem is that of periodically replenishing the stem cell pool via cell therapy. While stem cell research is much more advanced than that relative to the other categories discussed here, SENS runs a few related projects nonetheless.

>> RepleniSENS on sens.org >> >> Stem cells on Fight Aging! >>

ApoptoSENS: Fighting cellular senescence

Cellular senescence is the state of a cell that is no longer able to replicate, but rather than being disposed of as it should be, it stays right where it is, secreting toxic chemicals that are bad for other cells, favouring inflammation and the formation of cancer. Even though a moderate amount of senescent cells is good for you (because, for example, they play a role in wound healing and, paradoxically, they help preventing cancer, but I stress again that this is true only if they’re not too many), in old age their numbers are too high and they end up causing pathologies. A particular case is their role in immunosenescence, that this the decrease in functionality of the immune system during old age: specialised T-cells become too numerous with age and prevent new T-cells to specialise against new pathogens, thereby affecting the efficiency of the immune system.

If senescent cells don’t die when they should, it goes without saying that the answer is forcing them to die anyway, inducing them to undergo apoptosis (the so-called ‘programmed cell death’). Apoptosis happens spontaneously when necessary, though it is possible to induce it using senolytic drugs or suicide genes.

>> ApoptoSENS on sens.org >>

>> Senescent cells on Fight Aging! >>

>> Adaptive immunity on Fight Aging! >>

>> Native immunity on Fight Aging! >>

GlycoSENS: Breaking extracellular cross-links

A process known as glycation—that is blood sugar reacting with some kinds of proteins—results in the creation of extracellular cross-links, also known as advanced glycation end-products, or AGEs for short. AGEs cause loss of elasticity in tissues; for example, in old age they can lead to the stiffening of the arteries, which in turn can easily lead to strokes.

To solve this problem, it is necessary to find and use AGE-breaking molecules. SENS has been working on several papers and projects on the subject.

>> GlycoSENS on sens.org >> >> Extracellular cross-links on Fight Aging! >>

OncoSENS: The last line of defence against cancer

At the end of our chromosomes, inside the cell nucleus, are the so-called telomeres—’pieces’ of DNA that prevent chromosomes from deteriorating. Normally, during cell replication telomeres shorten, until eventually they become too short and their cell is no longer able to divide. Stem cells have access to telomerase, an enzyme that allows them to replenish their telomeres. This enzyme should not be available to other cells; oncogenic mutations to cell DNA can turn normal cells into cancer cells able to access telomerase, thus allowing them to divide uncontrollably. A few cancer types use a different, poorly understood mechanism to replenish their telomeres, the so-called ALT, or alternative lengthening of telomeres, that does not require telomerase.

The solution to the problem of cancer could be WILT, i.e. Whole-body Interdiction of Lengthening of Telomeres. In order to implement WILT, it would be necessary to delete the telomerase gene (and the ALT gene, whatever that may be) from the whole body; this would eliminate a necessary condition for cancer survival. However, this implies stem cells would not have any telomerase to replenish their own telomeres, which eventually would lead to generalised cell loss. To obviate to this side effect, it would be necessary to periodically replenish the stem cell pool with stem cells with sufficiently long telomeres—this kind of intervention would fall under the RepleniSENS category. Aubrey de Grey himself has repeated time and again that WILT is an extreme and dangerous solution; SENS is working on it only as a back-up plan, should other promising approaches (such as immunotherapy) turn out to be dead ends. WILT is also referred to as OncoSENS.

>> OncoSENS on sens.org >> >> Nuclear mutations on Fight Aging! >>

Important notes

So, is this all? Not quite. There are a few things we should keep in mind.

  • No therapy is perfect. Even if we implemented all seven components of SENS, we can’t expect they will all perfectly fix what they’re supposed to fix. Particularly, early versions of these therapies will be rather primitive and only partly working. There’s no reason to wallow in despair, though, because this will be more than enough so long as subsequent versions of the therapies will be more and more refined. To put it simply, suppose SENS 1.0 is able to rejuvenate a 70-year-old by 20 years only. This person will be 70 chronologically speaking, but 50 biologically. It’s something, although not quite the same as being biologically 25 again. Twenty years later, our hypothetical patient will be chronologically 90, but biologically 70; if, in the meanwhile, we developed a new version of SENS, say 2.0, which is able to turn back the biological clock by 30 years, the patient can undergo the new treatments and thus be biologically 40 while being chronologically 90. If we repeat the process periodically, each time with more effective ‘versions’ of the therapies that are able to fix more damage, we may reach the so-called longevity escape velocity, i.e. our average life expectancy will grow faster than time is passing—for example, with each passing year our average life expectancy could grow by two years. At the moment, our average life expectancy grows by much less than a year per year.

    (If you’re concerned about how the therapies would be administered, have a look at this article.)

  • Damage categories might be more than seven. Aside from different categorisations and disagreements over what processes do or don’t contribute to ageing, it is possible that other, presently unknown types of damage may cause age-related pathologies. None has been discovered in the last 30 years, which is definitely good news; however, there might be an eighth category of damages accumulating so slowly that they do not cause any appreciable symptom before—say—the 150th year of life or so. We don’t know, because no one has lived that long yet, but it is at least conceivable. Thus, even if we repaired all damages of the seven categories here listed, there might still be other unexpected problems to fix farther down the road. At any rate, it’s better not to cross our bridges before we get there and concentrate on fixing problems that are known; we will deal with any eventual new problems if and when they’ll manifest. (After all, as long as these problems are unknown and hypothetical, we don’t really have an option.)
  • Research is not as fast-paced as it could be. To a lot of people, the idea of curing ageing still feels like something impossible or anyway undesirable. As a result, funding for this kind of research, albeit it increased significantly as of late, is still insufficient. If the funding was adequate, we could have first-generation therapies within thirty years in a worst-case scenario. To secure larger funds, both public and private, it is imperative that rejuvenation becomes a mainstream topic, that its benefit are explained in detail, and that doubts and concerns of the people are addressed. This is the reason why I joined the other advocates and launched this website.

This not-so-brief account of SENS is rather simplified. If you’re a biologist or an expert of the field, you might have cringed at it more than once. For a far more detailed treatise, I definitely recommend you to read Aubrey de Grey’s Ending Aging. If you have any technical questions, I advise you to ask them to Aubrey de Grey directly; I know from experience he’ll gladly and promptly answer your questions.

It’s important to keep in mind that not all experts agree on the SENS categorisation of damage. The most notable example—which nonetheless vouches for the scientific validity of the SENS approach—is the classification presented in the by now largely known open-access paper Hallmarks of Aging, published on the prestigious journal Cell in 2013. As a friend of mine likes to say, Hallmarks is basically “SENS on steroids”: It includes the SENS categorisation (though it reorganises it a bit differently) and expands upon it adding a couple more factors, for a total of nine damage categories, for each of which the authors suggest possible interventions. A good, short introduction to Hallmarks can be found here. It is yet uncertain whether SENS or Hallmarks is the right categorisation, but all that matters is that scientists of the field are finally joining forces to declare total war on ageing. SENS is an excellent model to explain the situation to newbies, but in order to remain as neutral as possible as to what is the ‘right’ approach, on this website I will always use the more general term ‘rejuvenation’ or other similar terms.

A brief history of SENS

SENS’s past is a bit turbulent. The idea of a maintenance approach to ageing has always been very controversial ever since it was introduced to the field of gerontology in late 2000. Back then, the idea we could repair the damage caused by ageing was considered outrageous nonsense; indeed, SENS was initially met with perplexity and scepticism when not with outright derision and hostility. Top top it all, Aubrey de Grey—the beating heart of SENS—was originally a computer scientist; he switched fields when, to his utter horror, as he likes to say, he found out that nobody seemed to give a damn about curing ageing. After studying on his own for years and participating to innumerable conferences, he published a book on the free-radical theory of mitochondrial ageing, which earned him a PhD awarded by Cambridge University. De Grey’s original background has certainly contributed to the initial scepticism of other gerontologists.

Whilst today SENS is ever more popular and SRF works with several universities and research institutes on a plethora of projects—for example the Buck Institute for Research on Aging, which SENS works with on neurodegeneration and cellular senescence—the past didn’t look so rosy. In 2005, the MIT Technology Review magazine threw the so-called SENS Challenge: an explicit invitation to researchers to write a paper to prove that ‘SENS is so wrong that is unworthy of learned debate’, and offered 10.000$ to whomever would successfully do so. The Methuselah Foundation—an organisation co-founded by de Grey which SENS eventually spun off of—where so sure of themselves that they added another 10.000$ to the prize. Several papers were submitted to a neutral panel of judges, but only three of them where deemed relevant. Of these three, none—I repeat, none—won the prize. The judges’ unanimous verdict was that none of the articles managed to convincingly prove what they set out to prove, and some of them were even ‘too quick to engage in name-calling’. In particular, one of the judges commented: “I have no confidence that they [the authors of the criticism to SENS] understand engineering, and some of their criticisms are poor criticisms of a legitimate engineering process.” (Note that, indeed, SENS is essentially an engineering process applied to biology.) The judges also said that the proponents of SENS had failed to make a compelling case for it, and thus their final verdict was basically “we’ll see what happens”. I care to emphasise that this happened over ten years ago, over the course of which more and more evidence in favour of SENS has kept piling up. If you want to know more, I recommend you to check out this article about SENS and this one about de Grey. The state of the art of SENS as of 2017 is discussed here.

Next: What else can be done? >>

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