Mechanics of Aging and Strategies for Engineered Negligible Senescence (SENS).

There are many known animals that have extraordinarily long life-cycles. And there are several well known that could theoretically live indefinitely. For instance, there is a microscopic freshwater organism called Hydra. Under observation, death rates are arbitrary, with no relationship to time. They die by infection, parasites, predators, or just plain misfortune; but not from gerontology. They have the inimitable capacity to indefinitely regenerate tissues. So, for a simple, small organism, it seems that nature has solved the aging problem. For this little creature, nature has overcome the process aging; or what is known in biogerontology as ‘senescence.’ Only meeting its maker from extraordinary causes.

Biological senescence is the process of cumulative changes to molecular and cellular structures that interrupt metabolism with the passage of time, resulting in gradual deterioration. This is characterized by the declining ability to respond to stress, increased homeostatic imbalance, and increased risk of aging-associated diseases.

The quality to circumvent or prevent such senescence; where death only takes place through third party intervention (disease, for example); is called ‘negligible senescence.’ The question is, what if we could understand senescence mechanics in higher, more complex organisms, such a fish, birds, manuals; even us Homo Sapiens? And then develop negligible senescence therapies that could slow, and eventually halt aging?

Well, there is one man to listen to here, Dr. Aubrey de Grey, a British biogerontologist, and his ‘strategies for engineered negligible senescence’ (SENS). Instead of merely elucidating the biochemical processes or remodelling the symptoms of age related deterioration (as in geriatrics), de Grey promotes a subsistence engineering approach, that asks what are the main categories of age-related biochemical damage, and how we can fix them?

de Grey uses an analogy here, ‘How long does a house last? If you take care of the house diligently, and quickly address any problem that comes up, the house can last indefinitely. If you don't take care of it, it won't last very long.’ Clearly, like a house’s up keep, it is quite impossible to eliminate all the sources of the ravages of time. But we are now beginning to understand what and how damage occurs. And further still, how to remedially reappear damage fast enough so it does not accumulate and cause health problems.

What is DNA? Reading a book like this, you may be further along than a basic grasp of what DNA is. However, it is the next level of comprehension where it begins to get interesting. Remarkable, because DNA mechanics is simpler than most people assume. DNA is a double helix string made up of so-called nucleotide base-pairs A-T; C-G, that encode for all living entities. A complete string of DNA is known as a Genotype. Genotypes express specific body designs otherwise known as Phenotypes. A willow tree or house fly are phenotypecal designs expressed from a particular genotype. From a genetic engineering point of view, DNA is a kind of chemical software code, or programming language for living things. Hence, stringing different DNA base-pairs together in distinct ways, and different organism emerge. With one sequence, a bacterium is the result. With another, an elephant. It is the same with any subcomponent of life, all the way down to individual proteins.

De Grey describe these causes of aging as the Seven Deadly Things: (1) cell atrophy, (2) death resistant cells, (3) nuclear DNA mutations,(4) mitochondrial DNA mutations, (5) intracellular junk, (6) extracellular junk, and (7) extracellular crosslinks:

Cell atrophy. Our bodies are programmed to replace cells when they expire, through constant regeneration using our natural supply of stem cells. Some cells such as bone last for years; others like blood cells, fade in weeks. In due course, the processes of cell substitution begins to diminish. This phenomenon especially afflicts the heart and brain; even muscle tone and mass. Clearly, this sets up a diminishing returns loop. Our repair systems diminish because our cells are replaced less efficiently. To repair this catch-22, two strategies are in R&D: vitalising the division of existing cells or traducing new cells.

Death resistant cells. Stubborn, gatecrashers that extend their salutation. There are three types of cell culpable here. The first are visceral fat cells. Cells that mount and accumulate around vital organs. The net result is a deficiency in our body’s ability to make use of nutrients from the stomach systems. Frequently leading to Type 2 Diabetes. The second class are so-called senescent cells, which have altogether lost their capacity to replicate. One fault of these cells is that they release perished and damaging proteins to healthy neighbouring cells. A third category is memory cytotoxic T cells. A kind of immune cell that builds up faster than other immune cells, in turn bullying other vital functional immune cells; ultimately causing disease. One solution in R&D is to stimulate the body’s immune system sensitivity to target and kill these kind of T cells.

Mutations in the DNA of a cell’s nucleus. Mutations become dangerous when they lead to malignant cells that self-replicate; a.k.a Cancer. One of de Grey’s preferred strategies for rending such mutations soulless is Whole-body Interdiction of Lengthening of Telomeres (WILT). Basically telomeres (a type of gene a region of repetitive nucleotide sequences at each end of a chromatid, which protects the end of the chromosome from deterioration or from fusion with neighboring chromosomes. Telomere regions deter the degradation of genes near the ends of chromosomes by allowing chromosome ends to shorten, which necessarily occurs during chromosome replication) need to be a certain length for a cell to self-replicate. If the telomeres are too short, the cell goes into red alert and self-destructs.

When cancer hijacks the body’s cells, the cancer cells replicate so rapidly that their telomeres shorten quickly. But cancer cells have a devious trick to avoid destruction. By using the host cell’s protein synthesis machinery, they build enzymes that extend their telomeres, promoting incessant self replication. The WILT strategy, removes the actual DNA that contain the data essential to synthesize such enzymes…. Kurpow!

Eliminating the genes fundamental to the production of telomeres means that cancer cells will self-destruct before becoming life-threatening to the host, effectively offering a solution for a cure cancer.

de Grey admits that this is one of the most ambitious strategies of the SENS plan. The R&D here has already had a degree of success in mice. But when this therapy is a proven cure for cancer in mice, a therapy that works for humans will – it is felt – attract huge moon-shot resources to achieve breakthroughs in drug design and application therapies.

Mutations in the mitochondria. Mitochondria is the Duracell Bunny of cells. Baton shaped organelles, considered a cell’s power generator, converting oxygen and nutrients into adenosine triphosphate (ATP), the chemical energy currency that drives a cell's metabolism.

Only, when a gene is flawed or damaged, mitochondria crash and burn. Hence no fuel for the cell. One problem is that mitochondrial DNA is especially susceptible to free radicals, which compromises the DNA, potentially causing it to mutate.

Mitochondria are made of many thousands of proteins. Fortunately, only 13 of the proteins are manufactured using the DNA of the mitochondria itself. The rest are synthesized in the nucleus and conveyored in. The answer is to move the critical genes from the mitochondria to the nucleus of the cell. R&D is under way using lab mice and experimental gene therapy to add supplementary genes, improving the process.

Intracellular junk. Cells synthesize, make use and dismantle many thousands of molecules during the course of their life. But every so often a cell ends up with a rouge molecule so huge or unusual that it has trouble breaking it up. If a molecule cannot be broken, it stays there forever like a spanner in the work. Clearly, in the case of eye or heart cell, and even some nerve cells, this can cause life wrecking diseases such as Alzheimer’s, macular blindness, and atherosclerosis.

One SENS R&D scheme to onslaught intracellular scrap, is to kit and fit an incinerator enzyme called  lysozyme with extra bespoke enzymes, increasing the variety of molecules that it can torch, then lunching on and digest really odd or even super-large molecules.

Extracellular crosslinks. This is one of the most prevalent causes of age related damage. Picture under an electron microscope mounds of latticed molecular debris heaped up like a stinking rubbish tip on the surface cell. The molecular mounds entangle healthy proteins that would otherwise glide over other proteins. This leads to the most visible effects of aging such as rifts and wrinkles in tissues. Only, such crosslinked molecules have highly differentiated chemical structures than normal healthy tissue structures. One idea is to find or create enzymes that picks out this differentiation, breaking down the extracellular crosslinks while leaving the rest alone.

General extracellular junk. Superfluous molecule junk that just drifts around like space debris. Such armloads are notably found the brains of people with Alzheimer. Again R&D to stimulate the body’s immune cells to clear out these molecules has a strong overlap between treatments for Alzheimer’s and atherosclerosis and anti-aging treatments that address this cause. So there seems significant momentum in the right direction here.

Today, senescence is by far the leading cause of death. Greater than all current wars, accidents, infectious disease, and congenital disorders. On the order of 150,000 people die each day, that is ~100,000 per day expire of age mechanics wearing out. The big bottom line for all this clever, convoluted science, both commercially and morally, is that if de Gray’s seven deadly things of aging were eliminated, people could live a lot longer. If we R&D medicines and therapies that can clean up this damage, we could extend our lifespan to great lengths and achieve negligible senescence in humans.

From the standpoint of the human body, aging is much like a disease. A life- demolishing biochemical trend. And like most illness these days, aging is treatable. And this worldview is primarily due to lack of precedent, the simple complexity, and the feeling of certainty about aging that only quite lately we are starting to think of aging as a disease.

de Gray again,‘By 2025, worldwide average life-span will be extended by one year per year. Only 15 percent of deaths worldwide will be due to naturally occurring infectious diseases. The race for genetic enhancements will be what the Space Race was in the 20th Century. Genetic therapies and biomedical enhancements will be a multibillion-dollar industry. New techniques will enable doctors to change your DNA to revitalize old or diseased organs, enhance your appearance, increase your athletic ability, or boost your intelligence.’

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