Strategies for Engineered Negligible Senescence (SENS)

LysoSENS and MitoSENS are the current beneficiaries of funds raised by The Longevity Medical Research Fund. They are efforts to implement four of the seven Strategies for Engineered Negligible Senescence (SENS) for combating age-related pathology.

The basis of ENS strategies is to target by-products of necessary metabolic processes that are normally benign, but with time reach a threshold leading to a cascade of bodily malfunction and ultimately death. A tremendous opportunity presents itself, to progress age-related medicine beyond treating aging disorders distinctly, treating them instead as a collection of syndromes tied together by a few common threads. SENS aims to accomplish this by repairing the damage and breaking down the aggregates that serve as the intermediaries between metabolism and age-related diseases.

These strategies would therefore neither impede aging (Treatment "A") nor cure age-related disease (Treatment "B"). (Flattened arrows imply impedence.)

SENS therefore sidesteps our ignorance about the tremendous complexity of how metabolism causes aging, on the left side of the diagram. In fact, intervening at the level of damage/aggregate precursors appears to be an easier assault on the ill effects of aging than attempts to slow aging by intervening in the metabolic process. Ironically, rejuvenation may be far more achievable than stopping aging.

Furthermore, SENS avoids the enormous length of hundreds of age-related pathologies on the diagram's right. In fact, treating age-related pathology as a single targeted entity may be easier than addressing the large catalog of such diseases one by one.

Metabolic Processes	Intermediaries	Age-related Pathologies
Respiration (oxidation) Carbohydrate metabolism (glycation) Cell turnover (mutations, telomere shortening, disregulation, stem cell depletion) Etc....	Toxic buildup -Intracellular -Extracellular Mutations -Chromosomal -Mitochondrial Protein Crosslinks Cell death -Good Cells Die -Bad Cells Don't	Alzheimer's Dementia Atherosclerosis Arteriosclerosis Cancers Stroke Type 2 Diabetes Hormone decline Menopause Immune decline Pneumonia Osteoarthritis Blindness Hearing Loss Renal Failure Hypertension Vascular Disease Cardiac Weakness Cardiac Failure Etc....

LMRF therefore is not just supporting a disease-by-disease effort, but also what may prove to be an effective assault on the full bulk of the ill effects of aging. Because of the preventative nature of SENS, gerontological treatment may become far cheaper and more effective. Because SENS would address pre-symptomatic precursors of pathology, gains in longevity would be preceded -- and driven -- by gains in quality of health. Longevity would not be achieved for longevity's sake, without regard for quality of health. Life extension would instead be conditional on improved retention -- or rejuvenation -- of youthful health.

Basic SENS Premises

To enumerate some of the basic premises on which the ENS strategies above are based:

Axiom 1: Somewhere along the chain of events between metabolic processes and age-related diseases exist optimal points of intervention -- a point of minimum complexity forming a sort of bottleneck -- that balance the competing goals of keeping suffient distance from both our ignorance of how metabolism initially causes aging and the complexity of the resulting cascade of age-related pathologies.
Axiom 2: Amelioration of all damage and aggregates at such a bottleneck would prevent most or all of the ill effects of aging, without having to fully map the chain of reactions from each precursor at said bottleneck to each disease.
Axiom 3: Such a bottleneck is characterized by damage and aggregations that -- normally benign, thus not selected against by evolution -- become harmful after reaching a certain threshold.

Presumed benefits of strategies based on these axioms:

- Alternative treatments to age-related pathologies would arise;
- Addressing precursors that accumulate slowly means medical treatment would be infrequent, even making temporary side effects more worthwhile;
- The preventative nature and infrequency of treatment would significantly reduce medical expenses; and - Not having to map precursors to pathologies 1-to-1 would allow much current knowledge about aging to be used in a clinical setting without waiting decades for full understanding of aging.

This last point is where the E (for "engineered") in SENS comes from. Engineering doesn't always require perfect knowledge of a subject at the basic science level. Ancient Romans didn't need to know calculus to make arch-supported, gently sloping aqueducts that have stood for centuries. Edison didn't use reference tables on materials melting points to make an effective light bulb (depsite their availability!). Aspirin was used for decades before Nobel-winning research showed how it works. In this spirit ENS strategies have been developed with a keen eye for ways to work around blind spots in the current state of gerontological knowledge.

Only Seven?

Do all the ill effects of aging really have only seven precursors? It seems to be the case for the normal lifespan. Each intermediary listed below has been known about for at least a couple of decades.
Toxic buildup

- Intracellular

- Extracellular

Mutations

- Chromosomal

- Mitochondrial

Protein Crosslinks

Cell death

- Good Cells Die

- Bad Cells Don't

The stability of this list over time is indicative of its completeness. (See here for other aging theories that SENS has outlived.) At age 150, other usually benign conditions may become problematic -- non-cancerous chromosomal mutuations for instance. (For now, the chromosomal mutations that lead to cancer are by far the most important.) By then, researchers will hopefully find solutions. Until this becomes a problem though, first things first.

Click on any of the seven intermediaries to read about the strategy to address each.

The one intermediary for which LMRF promotes a "Treatment B"-type (post-symptomatic) approach over a precursor approach is cancer. Currently antisense RNA technology in clinical trials has demonstrated a remarkable ability to cure a range of previously incurable cancers -- without side effects.