Strategies for Engineered Negligible Senescence

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Strategies for Engineered Negligible Senescence (SENS, in German about "Strategies to make the aging process negligible by technical means") is a project by the biogerontologist Aubrey de Gray , which aims to repair the damage we call aging . For each of the known damage classes, which he calls the “seven deadly sins of aging”, he suggests strategies for combating them. These seven damage classes were discovered between 1907 and 1982, and no new ones have been added since then .

Damage classes

The SENS method proposed by de Gray is based on seven points of attack that he propagated. The author has identified gradually increasing changes in the body over the lifespan as points of attack which, based on rational considerations and preliminary experimental findings, can be regarded as a potential cause of aging. As is the case in such an early stage of research into many diseases, it is not entirely clear whether the observed changes really function as primary causes, are secondary events or actually develop independently of the disease process.

  1. In cancer (the deadliest consequence of mutations ) the strategy is to use gene therapy to delete the genes for telomerase and to eliminate telomerase-independent mechanisms that turn normal cells into "immortal" cancer cells. To compensate for the loss of telomerase in the stem cells , we would add fresh stem cells approximately once every decade, depending on the tissue.
  2. In the case of mitochondrial mutations, the plan is not to repair them, but to prevent damage caused by the mutations by using gene therapy to move modified copies of the mitochondrial genes into the cell nucleus . The mitochondrial DNA experiences a high degree of mutagen damage because most of the free radicals are created in the mitochondria. A copy of the mitochondrial DNA in the nucleus will be better protected from free radicals and better DNA repair will take place when damage occurs. All mitochondrial proteins would then be imported into the mitochondria.
  3. To remove intracellular waste, novel enzymes would have to be used, which may be obtained from soil bacteria that can break down the waste ( lipofuscin ). Enzymes naturally occurring in the human body cannot break down this substance.
  4. Extracellular waste (such as amyloid ) could be eliminated through vaccinations , which induce immune cells to “eat” the waste.
  5. Protein crosslinking can largely be reversed by drugs that break the links. However, in order to break some of these links, the development of enzymatic methods is likely to be necessary.
  6. In the case of muscles, cell loss can be repaired (reversed) through appropriate training . Other types of tissue would require various growth factors to stimulate cell division and in some cases stem cells would be needed.
  7. Aged cells could be removed by turning the immune system against them. Or they could be destroyed by gene therapy , by introducing “suicide genes ” that specifically kill aged cells.

Basically, de Gray suggests eliminating this damage afterwards instead of trying preventively to establish a metabolism that is as harmless as possible. For organizational reasons, among other things, since "aging per se" is not recognized as a clinical picture and clinical studies are not approved by the regulatory authorities. In addition, long-term, profitable intervention in the existing metabolic processes of the body would require a very deep and complex knowledge of them, which is by no means available today.

The specific metabolic processes that are ultimately responsible for the damage classes listed above are still only partially understood. But such profound knowledge is not absolutely necessary to counteract the structural deterioration with appropriate therapies. The strategies for their removal or repair are either already available in the form of prototypes or it is at least foreseeable how they could be developed from existing scientific techniques. But even after these new therapies (yet to be developed) have been used to repair aging tissue, metabolic processes will continue to cause new damage. This simply means that rejuvenating biotechnologies are not a one-off solution, but rather must be repeated at regular intervals in order to maintain the youthful function of tissues, organs and body. De Gray argues that there is no point in spending the vast majority of our medical resources on fighting aging diseases without fighting aging itself.

Nuclear DNA mutations / epimutations

Environmental toxins, viruses , radiation and errors in cell division lead to changes in the DNA of the cell nucleus. Apart from cancer , these mutations would have no relevant impact on life expectancy in de Grey's opinion within our current lifespan . The mutation rate in cells of young people is very low, in old age it increases by a factor of two to three, but the resulting value is still acceptable due to the low base size. Usually only 10% of the DNA in a cell is said to be active, which means that nine out of ten changes do not affect the cell's function. If an active gene has been damaged, this usually only leads to a deterioration but not to a complete standstill of the associated metabolic process. It is also important that the DNA changes only affect the one changed cell and its descendants generated by cell division.

It has been observed that the epigenetic profile in larger tissue structures in older people differs from those in younger people. Mainly there is a tendency towards pro-inflammatory and antioxidant activation. The nature of the changes and the extensive homogeneity of the change in the tissue suggest that this is an epigenetic reaction to primarily changed environmental conditions. So this is not a cause of aging, but a secondary process.

Cancers

The treatment of cancer always has a fundamental problem: the administration of a tumor-fighting drug does not kill 100% of the cancer cells in the vast majority of patients because some of them do not respond to the active substance. The remaining cells grow back into a tumor that is insensitive to the drug due to its previous selection.

Cell division in healthy tissue versus cancer

One would have to develop an active ingredient that has a goal that must be active in every cancer cell. The enzyme telomerase , which enables cancer cells to divide indefinitely by regenerating the telomeres necessary for division , would be a potential target. In addition, it would have to be ensured that every cancer cell is reached by the active substance. According to de Greys, this is only possible by non-selectively switching off the telomerase gene in all body cells through gene therapy, which is active in healthy stem cells as well as in cancer cells.

As a result, the stem cell reserves present in various tissues would be used up over time (approx. 10 years) and would have to be therapeutically replaced. Replacing stem cells in bone marrow has already been tried and tested in humans, but it is still associated with high risks. The regeneration of the skin surface from stem cells has already been successfully demonstrated in animal experiments. This is also easily accessible and therefore appears to be relatively easy to treat. Supplying stem cells to the other tissues in which stem cells would also have to be replaced, such as the inner lung tissue or in the gastrointestinal tract, poses a significantly greater difficulty. Despite the enormous effort, de Gray regards this intervention as justified because no other method is reliable able to reliably stop cancers, which increase with age.

Replacing stem cells (bone marrow puncture)

Mitochondrial mutations

In the mitochondria , the universal energy carrier ATP is produced from food and oxygen via a chain of chemical processes . Parts of the proteins required in this process are encoded by DNA that is not - as is usually the case - in the cell nucleus, but in the mitochondria themselves. Their local connection to the energy production process, which is connected with the formation of free radicals, as well as a lack of chemical protection and less effective repair mechanisms make the genetic material susceptible to mutations.

When comparing the lifespan of different species of the same size and body temperature, a correlation between lifespan and the degree of mitochondrial mutation can be seen. Free radicals and their effects in the mitochondria are associated with various chronic diseases (adult diabetes, Parkinson's disease, Alzheimer's dementia).

A calorie-restricted diet has been shown to extend the life span of model organisms. This observation can be attributed to a change in the metabolism in the mitochondria - which in this form produces fewer free radicals.

Intracellular waste products

With the lysosomes, animal cells have their own facility for breaking down substances that are no longer required, which are then converted into reusable basic building blocks. Materials are recycled that were only used temporarily and are basically useful, but have a defect and toxic compounds. In some cases it may happen that materials cannot be recycled or not fully recycled; this so-called lipofuscin (LF) then accumulates as a waste product in the cell over its lifespan.

In studies on species that lived for different lengths of time, it could be shown that the LF levels in the respective phases of life (youth, adult, age) were similar, although the calendar age in the phases of life (for example: species 1 is 2 years old, species 2 grew up at 3 years of age) was different. When cells divide, LF is divided between the two resulting cells, which reduces stress. However, this relief does not take place in the sensitive tissue of the heart muscle and brain, because the cells there do not divide. Large amounts of LF lead to reduced enzyme mobility and too low an acidity in the lysosomes, which makes the conversion process difficult.

De Gray assumes that intracellular deposits from LF play a role in many aging diseases such as arteriosclerosis, neurodegenerative diseases and macular degeneration .

Extracellular waste products

In the course of life, potentially harmful waste products accumulate outside of our cells in every human being. The best- known example is Alzheimer's disease , which is characterized by the formation of so-called amyloid plaques.

Alzheimer's disease progression, neuronal death, and the formation of neurofibrillary tangles and beta-amyloid plaques

Potentially fatal diseases can result from accumulations in the cardiovascular system. The deposition of protein fibrils around the muscle fibers of the myocardium causes the heart muscles to stiffen (restrictive cardiomyopathy). This leads to cardiac insufficiency via a rapid deterioration in the heart's pumping capacity. Due to the deposits, the heart walls are thickened with normal or reduced size of the heart chambers. - Such pathological changes may be the leading cause of death in people older than 110 years .

Protein chaining

Proteins are rearranged through a chemical reaction chain ( glycation or connection with triglycerides ) and thus tend to clump together and form chains. Diabetes sufferers are more affected because of the increased sugar concentration in their blood. In the cardiovascular system, this generally leads to a reduction in elasticity and flexibility in the tissue. Specifically, this means a reduced pumping capacity of the heart and, due to the hardening of the arteries, a contribution to the age-related increase in systolic blood pressure - both risk factors for a heart attack . Lack of elasticity in the vascular system of the brain increases the risk of cerebral haemorrhage under stress. Glycation damage also occurs in the eyes and kidneys; both organs are particularly badly affected in diabetics. Too many connections between the collagens cause the skin to age.

Opened aorta with reduced elasticity and flexibility in the tissue

Studies between different species and several individuals of a species show an inverse correlation between maximum lifespan and the degree of glycation of certain proteins (pentosidine). In humans, it has been shown that a higher blood sugar level (also within the normal range) leads to an increased risk of death - with different triggers. In humans, the two modified end products Glucosepane (around 20%) and K2P seem to make the largest contribution.

Replacement of lost tissue

The human body is basically able to repair damaged tissue using adult stem cells . In practice, however, the regeneration potential is limited. In the case of a stroke, it has been shown that stem cells in the brain actually migrate to the damaged area; there, however, 80% of them die within a few weeks. The remaining 20% ​​can only restore 0.2% of the damage. In animal models of various diseases, embryonic stem cells were able to renew the affected tissue to a significantly higher degree. Their potential to divide is significantly greater and they are able to produce all cell types. Regenerating the thymus could improve the performance of the immune system. In addition, cell therapies have a good chance of success in many age-related diseases such as heart attacks, strokes, Parkinson's and macular degeneration.

Superfluous cells

Cell types can arise in various types of tissue in the body that are not particularly dangerous in themselves, but no longer work optimally or can negatively influence processes through excessive occurrence. At least they occupy the place where new, healthy cells would normally appear.

The immune system has at any given stage of life a contingent of cells that can sustain it. Among them are the innate immunity system, cells that embody the acquired immunity and memory cells that provide rapid defense against known antigens. In the case of chronic infections that the immune system can only suppress but not completely eliminate, such as herpes simplex, herpes zoster, or the cytomegalovirus , the immune system is permanently active against these pathogens. This means that a certain contingent in the immune system is used up for this permanent position battle, which can lead to deficits elsewhere. It has been observed that over time the effectiveness of immune cells dealing with chronic infection decreases. In addition, the chronically activated cells stand in the way of regular work for other tasks of the immune system.

Lymphocyte , immune cells which, in a senescent state, can negatively affect the immune system through excessive occurrence

Adipose tissue is not to be seen as a pure energy store, but has functions like an organ. Fat cells come from the same precursor cells as macrophages and can release inflammatory messenger substances such as TNF- alpha or IL- 6 . The involvement of obesity in the development of serious diseases such as diabetes has been well researched; the excessive accumulation of fatty tissue around the internal organs seems to be particularly unfavorable. Differences in the effectiveness of insulin utilization between older and younger people are much smaller when the subjects of both groups are the same in terms of the amount of organ-surrounding fat. Conversely, liposuction, which only removes subcutaneous fat, did not have a positive effect on insulin utilization.

After several divisions, the life cycle of the cell is coming to an end; in the end, the cell usually eliminates itself. In some cases this mechanism does not work and the aged cells try by all means to maintain normal function. They produce substances such as EGF, MMPs, SDF1, VEGF, which in high concentrations could promote cancer growth.

In 2009, Aubrey de Gray co-founded the SENS Foundation to drive advances in the areas listed above, both through research and through public advocacy and the fight against prejudice.

Advances to date in repairing molecular / cellular damage

Cell loss

Aged cells

In order to switch off these unwanted cells, it is proposed to use modern methods, as they are known from cancer medicine. If unique characteristics of the cells to be switched off are found, a drug can be developed in the laboratory that selectively binds to these cells and only has its effect there - in this case, the destruction of the cells. Because of the precise selection, these methods are relatively low in side effects and yet very effective.

In Dr. Janko Nikolich-Zugich at Arizona University , the relationship between persistent viral infections and immunosenescence was researched in 2010 and T cells from young adult mice were transplanted into older mice that had had some of their own sensitive T cells removed.

Protein crosslinking / glycation

An Indian company called Torrent Pharmaceuticals has been developing a molecular cocktail for some time (2006) to break down AGEs and remove the vascular and tissue adhesions associated with diabetes.

The active ingredient alagebrium , which is supposed to improve the performance of the cardiovascular system by breaking down these chains, has shown encouraging results in a large number of studies on different experimental animals. By breaking down alpha-diketones, the flexibility of the tissue and clinical parameters such as blood pressure and the pumping capacity of the heart could be improved. Unfortunately, these hopeful results could not be confirmed in human clinical studies.

Aubrey de Gray suspects that methodological deficiencies in tissue analysis and a different composition of the modified end products in species that have lived for different lengths of time are responsible for this.

Extracellular waste

Tests on various animal models have shown that vaccination against amyloid is effective and safe. However, the first clinical studies on humans had to be stopped prematurely because of severe inflammation in the patient's brain. Passive vaccination, i.e. the regular direct administration of the desired antibodies, could offer a solution, as could active immunization against only partial elements of the amyloid.

After therapies successfully eradicated the accumulation of amyloid-β in the brain, research now (December 2013) focuses on hyperphosphorylated tau.

Intracellular waste

In laboratory experiments, bacteria could be isolated that form lipofuscin- degrading enzymes. These enzymes could be given in tablet form, infusion, or made directly in the cells by gene therapy.

In animal experiments on mice it could be shown that the functionality of the liver of older animals could be improved significantly (up to the level of young mice) by increasing the number of receptors on the liver cell surface to which chaperones can dock.

Mitochondrial mutations

In experiments on mice in 2005, an additional gene for the antioxidant enzyme catalase was implemented at various points. The uptake of the additional gene in the cell nucleus did not change life expectancy. However, through incorporation into the mitochondria, damage to their genetic material could be reduced and the maximum lifespan of the animals increased by around 20%.

To maintain one's own metabolism, NADH is converted to NAD + in modified mitochondria via the plasma membrane redox system. In the process, excess electrons are released into the extracellular area, where other, longer-lived molecules such as LDL cholesterol can be oxidized.

In 2011, researchers established Dr. Matthew 'Oki' O'Connor and Dr. Gayathri Swaminathan created several stable cell cultures in the laboratories of the SENS Foundation, for each of the five modified mitochondrial genes they work with.

Mutations in the nucleus

The SENS Foundation is funding research at the Albert Einstein College of Medicine to pinpoint the rate at which epimutations accumulate so that a further step can be taken against the mutations before they cause cancer.

At the same time, the SRF's in-house laboratory began in February 2012 to identify molecular targets (so-called mediators) in order to switch off the alternative telomere lengthening (in addition to telomerase ) in cancerous tumors .

Web links

Individual evidence

  1. ↑ Aubrey de Gray, Michael Rae: Never Old! This is how aging can be reversed. Advances in Rejuvenation Research . Transcript Verlag , Bielefeld April 2010, ISBN 978-3-8376-1336-0 .
  2. ↑ a b Szilard L: ON THE NATURE OF THE AGING PROCESS . In: Proc. Natl. Acad. Sci. USA . 45, No. 1, January 1959, pp. 30-45. PMID 16590351 . PMC 222509 (free full text).
  3. ↑ Cutler RG: The dysdifferentiation hypothesis of mammalian aging and longevity . In: Giacobini E, et al. (Ed.): The Aging Brain: Cellular and Molecular Mechanisms of Aging in the Nervous System  (= Aging), Volume 20. Raven, New York 1982, ISBN 0-89004-802-9 , pp. 1-19, OCLC 8473401 .
  4. ↑ Harman D: The biological clock: the mitochondria? . In: J Am Geriatr Soc . 20, No. 4, April 1972, pp. 145-7. PMID 5016631 .
  5. ↑ a b STREHLER BL, MARK DD, MILDVAN AS: GEE MV: Rate and magnitude of age pigment accumulation in the human myocardium . In: J Gerontol . October 14, 1959, pp. 430-9. PMID 13835175 .
  6. ↑ A. Alzheimer's: About a strange disease of the cerebral cortex. . In: Allg. Z. psychiatrist. Psych. Court Med. . 64, No. 1-2, 1907, pp. 146-148.
  7. ↑ a b MOVAT HZ, MORE RH, HAUST MD: The diffuse intimal thickening of the human aorta with aging . In: Am. J. Pathol. . 34, No. 6, 1958, pp. 1023-31. PMID 13583094 . PMC 1934788 (free full text).
  8. ↑ a b Monnier VM, Cerami A: Nonenzymatic browning in vivo: possible process for aging of long-lived proteins . In: Science . 211, No. 4481, January 1981, pp. 491-3. PMID 6779377 .
  9. ↑ BRODY H: Organization of the cerebral cortex. III. A study of aging in the human cerebral cortex . In: J. Comp. Neurol. . 102, No. 2, April 1955, pp. 511-6. PMID 14381544 .
  10. ↑ a b HAYFLICK L: THE LIMITED IN VITRO LIFETIME OF HUMAN DIPLOID CELL STRAINS . In: Exp. Cell Res . 37, March 1965, pp. 614-36. PMID 14315085 .
  11. ↑ Cutler RG: The dysdifferentiation hypothesis of mammalian aging and longevity . In: Giacobini E, et al. (Ed.): The Aging Brain: Cellular and Molecular Mechanisms of Aging in the Nervous System  (= Aging), Volume 20. Raven, New York 1982, ISBN 0-89004-802-9 , pp. 1-19, OCLC 8473401 .
  12. ↑ G. Witzany: The viral origins of telomeres and telomerases and their important role in eukaryogenesis and genome maintenance. . In: Biosemiotics . 1, 2008, pp. 191-206. doi : 10.1007 / s12304-008-9018-0 .
  13. ↑ Harman D: The biological clock: the mitochondria? . In: J Am Geriatr Soc . 20, No. 4, April 1972, pp. 145-7. PMID 5016631 .
  14. ↑ A. Alzheimer's: About a strange disease of the cerebral cortex. . In: Allg. Z. psychiatrist. Psych. Court Med. . 64, No. 1-2, 1907, pp. 146-148.
  15. ^ Coles LS, Young RD: Supercentenarians and transthyretin amyloidosis: the next frontier of human life extension . In: PREVENTATIVE MEDICINE . 54, No. Suppl, 2012, pp. S9-s11. doi : 10.1016 / j.ypmed.2012.03.003 . PMID 22579241 .
  16. ^ Searching for the Secrets of the Super Old . Science. Pp. 1764-65. September 26, 2008. Retrieved February 22, 2013.
  17. ↑ "Stem Cell Therapy for Paraplegics" , October 13, 2010
  18. ↑ SRF End of Year Report 2010 . Retrieved October 26, 2014.
  19. ↑ AGE Breakers Beyond Alagebrium . Retrieved October 26, 2014.
  20. ^ Ezio Giacobini, Gabriel Gold: Alzheimer's disease therapy — moving from amyloid-β to tau . In: Nature Reviews Neurology . tape 9 , no. December 12 , 2013, p. 677-686 , doi : 10.1038 / nrneurol.2013.223 .
  21. ^ The anti-aging garbage disposal. On: Wissenschaft.de from August 11, 2008.
  22. ↑ SRF End of Year Report 2011 . Retrieved October 26, 2014.
  23. ^ Epimutations at Albert Einstein College of Medicine . Retrieved October 26, 2014.
  24. ↑ Making cancerous mutations harmless . Retrieved October 26, 2014.