Guest Blog: Harold Katcher: Is Prevention of Ageing within our Grasp?

Introduction

Slowly but steadily knowledge about the human body has progressed and new ideas of animal ageing have immerged. The classic model of ageing, based on “accumulation of errors” has become an outdated notion. Instead, evidence suggests that ageing, at least in part, is likely the result of a failure in the function of cells (such as stem cells) required for cellular regeneration. Replacing impaired stem cells with fully functional stem cells should thus prevent/treat age-associated pathologies allowing us to live healthier longer lives.

What We Think We Know

We were once taught that the essential differences between animals and plants were that plants are mostly non-living, except for a layer or bud of special cambium cells, called meristems; unlike animals, plants grew from their outside surfaces and tips – while animals grew from the inside by the division of somatic cells. These notions have since been replaced with one in which specialized cells, called stem cells, (the animals' “meristematic” tissue) or progenitor cells (like stem cells, only less pleuripotent and of a limited lifespan), that can differentiate into, and replace, various diverse cell-types, (in contrast to somatic cells which cannot). (Janzen et al 2006). It has become clear that the many impairments of the ageing body are due to ageing stem/progenitor cell populations.

For example, muscle loss in the elderly (sarcopenia) appears to be the result of decreasing numbers of stem cells. (Hawke T.J..& Garry, D.J-. 2001). Muscle satellite cells which lie between the sarcolemma and the basement membrane of terminally differentiated muscle fibers, provide muscle precursor cells that are then incorporated into muscle fibers (Mauro, A . 1961). Satellite cells from aged individuals display an impaired proliferative ability when compared with satellite cells from a young individual, thus possibly resulting in sarcopenia. In organs like the liver that depend on progenitor cells for tissue repair and replacement, progenitor cell impairment would also result in deficiencies in wound healing and thus presentation of age-associated pathologies.

The loss of immune function, commonly observed within the elderly, makes them more susceptible to various diseases, infections and cancers. As in the case of ageing tissues, a lack of functional cells characterizes an aged immune system. Conversely, in this instance, stem cell populations do not decline, but instead there is an increase in the stem cell populations (i.e. hematopoietic stem cells, HSCs) that reside within the bone marrow (Sudo et al. 2000). However, unlike young HSCs, the ratio of the many potential cell-types that the HSC population generates changes with ageing. For example, aged HSCs move away from production of lymphoid line cells (T and B lymphocytes and NK cells) and towards the production of myeloid line cells (monocyte/macrophages, RBC, thrombocytes, granulocytes) cells. This age-associated reduction lymphoid cells, which forms the adaptive immune system, is thought to result in the age-associated decreased immune response (Chambers et al. 2007). The increased fraction of myeloid precursor HSCs appears to contribute to the myeloid leukemias that occur among the elderly (Rossi et al.).

So how can we combat the effects of functionally declining stem/progenitor stem cell populations? Solutions such as stem cell cloning and telomere elongation through telomerase therapy have been suggested, but is this really necessary? Is there a way to rejuvenate aged stem cells from within out own bodies, giving them the ability to constantly maintain high cell numbers in the organs they populate, cells with high proliferative capacity, rapid responses to wounding? It has become apparent that this possibility may exist.

A New Paradigm - Evidence accumulates

Several line of evidence suggest that the standard model of ageing, based on “error accumulation” is incorrect. Several studies in which tissues or organs are transplanted from donor animals have shown that the ability of the graft to be successful (by measures of ability to proliferate or recover from wounds) depends not on the donor's age, but on the age of the recipient. Such studies have shown that HSCs from aged immunodeficient donors gave normal responses in young recipients (Harrison et al 1977), and that aged HSCs could be coaxed to produce lymphoid cells by being placed together with young osteolineage cells (Mayack, S,R. And Wagers, A. 2008). Additionally, transplanted aged muscle responded to the internal environment of a young recipient by showing the same sort of wound- repair as young muscle.

The most important experiment investigating the effect of environment (specifically the humoral environment) was performed in 2007 by Irina Conboy and a later confirmation came with experiments performed by Mayack's group in 2010. While earlier in vivo experiments showed that tissues and organs obtained from aged donors could effectively be rejuvenated by being placed in the bodies of young recipients, it was not clear which factors were acting to rejuvenate these aged organs. Were there local tissue interactions, were there positive factors in young recipients that caused a revitalization of the old organs, or perhaps negative factors in aged bodies preventing cells from proliferating? Were cells from the young recipients colonizing these aged organs? How much did the environment of the aged cells influence their phenotype?

Conboy et al (2005) used a procedure called parabiosis (Finerty, J. 1952) to pair the circulatory systems of two mice. They now effectively shared the same blood, but not interactions between tissues of the parabionts (other than blood cells), thereby narrowing down the possible factors influencing the cells of the parabionts. In a nicely controlled experiment, mice were paired in either isochronic parabiosis or heterochronic parabiotic associations – in the isochronic cases two mice of the same age were tied together – either a young-young pairing or an old-old pairing and the heterochronous association a young mouse (2-3 months) was coupled to an old mouse (19-26 months) and were kept in this pairing for five weeks. After that time, it was found that in heterochronic pairings, but not in isochronic pairings old muscle satellite cells returned to youthful performance in terms of effecting wound healing and increased proliferative capacity. Another insightful experiment narrowed the range of responsible factors. In vitro experiments showed that exposure of aged cells to young serum was sufficient to rejuvenate aged HSCs, muscle satellite stem cells as well as liver progenitor cells. As the paired mice parabionts have distinctive chromosomal markers it was assured that the old organs weren't being colonized by young cells.

Further experiments extending the concept that the environment controlled the age-phenotype of the cell, was provided by Mayack et al (2010). Mayack used Conboy's method of parabiosis together with parallel in vitro studies using serum to provide the external environment. Both sets of experiments also showed that young serum was caple of rejuvenating aged HSCs. Mayack's group however showed that the cells rejuvenated by the young environment were the bone stromal cells. It was these rejuvenated stromal cells that later interacted with aged HSCs to set back their phenotypic-age. The parallel in vivo/in vitro experiments performed by these groups showed that the rejuvenation of cells was a function of a factor or factors carried in the serum. The explanations proposed; that either young blood diluted inhibitory factors present in aged blood, or brought new levels of stimulatory factors carried by young blood, or both.

While neither experiment could discriminate between these alternatives, both showed that the cells' environment was responsible for an ageing-phenotype (the panoply of genes expressed, its proliferative potential, various molecular markers of ageing). The one conclusion that can be taken for certain is that factors in the blood of the young animal were able to rejuvenate a variety of different stem/ progenitor cell lines in vivo, and that, in particular, as show by the in vitro experiments, factors present in the serum of young animals rejuvenate the stem and progenitor cells of aged animals. The conclusion reached by the groups involved in this research was that blood borne determinants, both positive and negative might be isolated, and eventually added to or removed from the blood of the ageing. So for the first time in history, there is a reasonable prospect to achieve what mankind has sought for all of history. There may finally be a therapeutic approach for the treatment of ageing and thus, disease. Evidence of such inhibitory factors in the blood of aged mice (McCay et al. 1957) and stimulatory factors in the serum of young mice (Hadad et al 1988), have already been detected.

Conclusions

The answers to extending healthy life span is now within our grasp – what if our own stem cells could be rejuvenated? With only the four cell types proven to be “rejuvenate-able”, (1) muscle loss could be eliminated, (2) the immune system made effective again, (3) bone now capable of making osteoblasts for growth and strength and (4) the liver able to perform its functions as in youth. Other cell types may also be positively influenced, leading to youthful changes such as, new hair growth, smooth skin, improved memory from neuron regeneration. The possibilities are endless. If viewed in this light, it is obvious what should be done – this new model should be tested and tested on people – and the means to test it? A practical medically approved procedure, cheap while being at the same time, able to provide all of the factors needed to rejuvenate cells is available right now! This is a procedure that any consenting physician could perform tomorrow.

I am not going to talk about it now – like all great secrets, once told it becomes obvious –“ no duh, why hasn't it already been tried.” Join me and we'll perhaps try it together. (hkatcher@earthlink.net.)

Papers of Interest

Chambers, S.M. et al. Ageing hematopoietic decline in function and exhibit epigenetic dysregulation. PLOS Biology (5) e201

Conboy et al. Rejuvenation of aged progenitor cells by exposure to a young systemic environment Nature (433) 760 -764 (2005)

Finerty, J. Parabiosis in physiological studies Physiol. Rev. (32) 277 – 302 (1952)

Hadad, E. J. et al Lymphocyte induced angiogenesis factor is produced by L3T4 murine lymphocytes and its production declines with age. Cancer Immunol Immunother (26) 31- 34 (1988)

Harrison et. al. Stem cell lines from an old immunodeficient donors give normal response in young J. Immunology (118)1223 – 1228 (1977)

Hawke, T.J. And Garry, D.J. Myogenic satellite cells: physiology to molecular biology J. Appl. Physiol (91) 534 – 551 (2001)

Janzen, V. et al. Stem-cell ageing modified by the cyclin-dependant kinase inhibit p12INK4a . Nature (443) 421- 426 (2006)

Mauro, A. Satellite cell of skeletal muscle fibers. J. Biolphys.Biochem. Cytol (9) 493 – 495 (1961)

McCay et al. Parabiosis between young and old rats Gerontologia; (1):7-17 ( 1957)

Mayack, S.R. et al. Systemic signals regulate ageing and rejuvenation of blood stem cell niches Nature (463)495-500 (2010)

Mayack, S.R. & Wagers, A Osteolineage niche cells initiate hematopoietic stem cell mobilization Blood (112) 519 – 532 (2008)

Rossi, D.G., Jamieson, C.H. & Weissman, I.L. Stem cells and the pathways to ageing and cancer. Cell (132) 681-696 (2008)

Sudo, K. et al. Age-associated characteristics of murine hematopoietic stem cells. J. Exp. Med (193) 1273 – 1280 (2000)