Initial Definition

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SENS concept

The SENS approach was first fully defined by Dr. Aubrey DeGrey in the book "Ending Aging", co-authored with Michael Rae.

The core of deGray's approach to combat aging is periodic repair of damage to cells accumulated over time. He defines his approach by contrasting it with two other approaches, preventive and curative. Preventive approach seeks to prevent the damage to the organism which results in aging. Curative approach seeks to cure the illnesses caused by the general degradation of the organism as the result of aging.

He argues that preventive approach is too complex, since the processes resulting in aging are the very same processes allowing us to sustain ourselves. He also argues that curative approach is not thorough enough to make a significant improvement to the lifespan, since it's dealing with the consequences of the damage done to the organism on the cellular level.

The SENS approach is designed to be the best of both worlds: it does not attempt to tackle the causes of the molecular damage, while fixing this damage instead of dealing with the consequences of it, as illustrated on the diagram below.

SENSDiagram1.jpg

7 types of aging damage.

DeGrey identified 7 types of damage which cause aging. If we could fix or render harmless this damage, we could bring the organism to the same state it was before it started aging, effectively stopping the aging process. The SENS approach therefore can be described as a comprehensive suite of rejuvenating technologies, periodically applied to aging organism in order to improve its functions.

Cell loss, cell atrophy.

Cell depletion is the loss of cells without equivalent replacement. It happens in some of our most important tissues as we age. The brain and heart are particularly affected but it can also affect our skeletal muscles.

The gaps in our long-lived tissues left behind by unreplaced cell loss are dealt with in different ways:

  • Sometimes they are filled by nearby cells getting bigger (as in the heart).
  • Sometimes they are replaced by other types of cell or by fibrous acellular material (this happens in the brain and the heart).
  • Sometimes they aren't filled at all, and the tissue just shrinks (this happens in muscle).

Junk outside cells.

Extracellular junk is aggregates of stuff that do not have any function and should ideally have been cleared out of the body, but have proven resistant to destruction. Extracellular junk is different from extracellular cross-linking - it refers only to substances that do not have any function, not even a biophysical one.

Most of this junk is termed "amyloid" of one variety or another. You may have heard of one form of amyloid - Abeta, the stifling, web-like material that forms plaques in the brains of patients with Alzheimer's disease, and also (more slowly) in everyone else's.

There are also a variety of similar aggregates that form in other tissues during aging and age-related diseases, of which the best-known is islet amyloid in Type II diabetes. A range of other amyloids feature in diseases called amyloidoses, which are found most commonly in people with unusual genetic disorders, but also begin to cause organ dysfunction in the very old. In fact, among supercentenarians (those who survive to 110 or older) the condition senile systemic amyloidosis is one of the biggest killers.

Crosslinks outside cells.

All the proteins inside our cells are destroyed and rebuilt quite regularly, as a way to keep them in a generally undamaged state. Sometimes these mechanisms are incomplete, but they are generally satisfactory.

Some of the proteins outside our cells, however, are laid down early in our life and then never recycled at all; while some others are only recycled very slowly. The proper functioning of the tissues composed of these structural proteins – the elasticity of the artery wall, or the transparency of the lens of the eye, or the high tensile strength of the ligaments – relies on their maintaining their proper structure. But chemical reactions with other molecules in the extracellular space occasionally result in a chemical bond (a so-called crosslink) between two nearby proteins that were previously free-moving, impairing their ability to slide across or along each other. This effect is especially prominent in the case of the artery wall, which becomes much more rigid as its proteins are crosslinked – leading to high blood pressure.

Death-resistant cells.

There are three main classes of cells that sometimes acquire a metabolic state that is damaging to their neighbours, and that accumulate in the body during aging:

  • Visceral fat cells

Fat cells tend to grow and/or proliferate with age due to energy imbalance, and often replace the muscle mass that we lose with age. Their relative danger depends upon where they occur.

Interestingly, the most conspicuous fat – the "subcutaneous fat" that accumulates under the skin, making a person "pear shaped" – seems to be relatively harmless, unless of course it gets to the stage known as "morbidly obese" in which its sheer weight and the strain it puts on the heart and joints become a harmful stress on the body.

By contrast, "visceral" fat (the fat that accumulates around the organs of the gut, causing an "apple shape") seems to be really bad for us. It promotes the progressive loss of our ability to respond to nutrients coming in from the stomach; in particular, it causes us to develop insulin resistance. This means that there is a diminished effect of the insulin's signal to the cells to absorb and store sugar from the circulation. Eventually, this leads to Type II diabetes.

  • Senescent cells

So-called "senescent" cells are those that have lost the ability to reproduce themselves. They appear to accumulate in quite large numbers in just one tissue (the cartilage in our joints), but even in these small numbers they appear to pose a disproportionate threat to the surrounding, healthy tissues, because of their abnormal metabolic state. Senescent cells secrete abnormally large amounts of some proteins that are harmful to their neighbours, stimulating excessive growth and degrading normal tissue architecture. These changes appear to promote the progression of cancer.

  • Immune cells

The effect of the third type of cells is more complicated to explain. In brief, the total number of white blood cells in our bodies seems not to change very much with age, but some subsets of them become more numerous and others less. The third type of harmful cell accumulation occurs in some populations of immune cells ("memory cytotoxic T cells", especially those that are charged with defending us against infection by the ubiquitous cytomegalovirus). These cells tend to lose their effectiveness over time, and simultaneously stop properly responding to the body's signals to clear out of the way to make room in the limited immunological "space" for other kinds of immune cells, resulting in a condition called immunosenescence. Immunosenescence is thought to be largely responsible for the weakened immune responses of the elderly (and thus their greater vulnerability to infections such as pneumonia and influenza), and for the reduced effectiveness of vaccines in the same group.

Hence, it is important to cull these cells back in order to make way for others to expand as needed – both young, healthy cells to defend us against cytomegalovirus, and also cells specialized in fighting other infections. Certain other types of immune cell seem also to become dysfunctional during aging, and again this may be because they've divided often enough that DNA damage responses are kicking in to stop them dividing much more, in order to prevent potentially cancerous cells from gaining a foothold.

Mitochondrial mutations.

The mitochondrion is a machine within the cell that acts as the "power plant" of the cell. Mitochondria take oxygen and chemically combine it with energy-rich nutrients from our food, to make carbon dioxide and water (which we exhale) and ATP, the "energy currency" of the cell.

The mitochondrion is therefore a really essential part of the cell. Lots of other parts of the cell are essential too, though, so why have a whole SENS strand devoted to it? The answer is that, unlike any other part of the cell, mitochondria have their own DNA (mtDNA), separate from the nucleus. Being at the site of cellular respiration, the mtDNA is vulnerable to its reactive by-products. Worse yet, the mitochondria's capacity for repairing DNA damage is much more limited than that of the nucleus. Thus we need a different system to combat the inevitable accumulation of such mutations.

Junk inside cells.

Cells have a lot of reasons to break down big molecules and structures into their component parts, and a lot of ways to do so. Unfortunately, one of the main reasons to break things down is because they have been chemically modified so that they no longer work, and sometimes these chemical modifications create structures that are so weird that none of the cell's degradation machinery works on them.

This situation is very rare, but in the long run these modified chemicals add up. Ultimately the chemicals end up in the lysosome, a special vessel that contains the most powerful degradation machinery in the cell. If something can't be broken down there, it just stays there forever. This doesn't matter in cells that divide regularly, because division dilutes the junk enough that it remains at harmlessly low levels, but non-dividing cells gradually fill up with this stuff, making them dysfunctional. The heart, the back of the eye, some nerve cells (especially motor neurons) and, most of all, white blood cells trapped within the artery wall all suffer from this.

Eventually, these cells can't process any more of this junk, and they stop working correctly. This failure is the key cause of atherosclerosis (the unstable buildups, called plaques, that build up in the artery wall and eventually burst, causing heart attacks and strokes). As the cells responsible for clearing toxic fatty materials out of the blood vessels become engorged with indigestible materials, they cease functioning and die, leaving their corpses behind to build up in the vessel. Failure to process recalcitrant junk within the cell is also important in several types of neurodegenerative diseases (such as Alzheimer's and Parkinson's) and in macular degeneration (the main cause of blindness in the old). So, it's very important that we find a way to prevent or reverse the build-up of these wastes within the cell.

In neurodegeneration, aggregates also tend to form in parts of the cell other than the lysosome. There is, however, good evidence that this is a compensatory measure when neurons' lysosomes stop working properly as a result of the more modest accumulation of lysosomal toxins. Therefore, if we fix the lysosome then the non-lysosomal aggregates should disappear naturally.

Nuclear [epi]mutations (only cancer matters).

Two types of change accumulate in our chromosomes as we age: mutations and epimutations. Mutations are changes to the DNA sequence itself whereas epimutations are changes to the "decorations" of that DNA, which control its propensity to be decoded into proteins. Luckily, we don't need to deal with these two phenomena separately, because we can render them both harmless in the same way. For brevity, the term "mutations" is used below to refer to both types of changes.

This is an area of aging in which evolution has done the really hard work for us. We have an enormous amount of DNA – about 3 billion base pairs – and the job of keeping it intact and functional is incredibly complicated. But, through evolution, the necessary sophistication has developed. We're particularly lucky in one way: evolution (since the emergence of vertebrates, anyway) has faced one DNA maintenance problem that is far bigger than all the others, and that is to stop organisms from dying of cancer. Cancer can kill us even if one cell gets the wrong mutations, whereas any loss of function in any genes that have nothing to do with cancer are harmless unless and until they have happened to a lot of the cells in a given tissue. Because the same maintenance machinery repairs and proofreads all genes – not just the ones that are more commonly involved in cancer – the fidelity of the entire code gets maintained at the very high standards that already keep us from getting cancer for many decades. So, even genes that don't usually contribute to cancer if mutated get a free ride; they are already maintained far better than we need them to be in anything like a normal lifetime. For rather esoteric reasons, this theory is called protagonistic pleiotropy (PP).

It's possible that non-cancerous mutations may still cause us some problems, such as mutations that kill cells in very small populations (where the loss of even a few cells can have a significant effect on function), or that cause cells to enter into a metabolic state that makes them toxic to their neighbours (so that damage to just a few isolated cells causes problems to normal, unmutated cells around them). However, these special cases need not concern us here because they are dealt with by other arms of the SENS platform: stem cell therapy and selective removal of toxic cells.

References

  1. de Grey, Aubrey; & Rae, Michael (September 2007). Ending Aging: The Rejuvenation Breakthroughs that Could Reverse Human Aging in Our Lifetime. New York, NY: St. Martin's Press.
  1. Research Themes. SENS Foundation. Retrieved 2012-06-30.