Stuart Calimport on the subject of SENS

Stuart Calimport, is a grad student at having studied Molecular Medicine at Imperial College London and Practical Ethics at The University of York . He is also a key volunteer for the Strategies for Engineered Senescence Foundation Academic Initiative.

Strategies for Engineered Negligible Senescence (SENS), by a more general definition, is an engineering strategy to reverse the effects of ageing via regenerative medicine. What it supposes is that ageing is bad (I use this term to describe negative things that reduce the complexity of complex systems) and so reversing ageing is desirable, reversing ageing is possible, and that we know just enough about ageing to cure enough of it to live a bit longer until we cure the next ageing related problem (Longevity Escape Velocity). The opposite of this viewpoint would be that ageing is a good thing, or that it is impossible to cure. This opposite view is very rarely held by gerontologists and other scientists, instead many say that ageing is bad and it is possible to cure, just not in the timespan suggested by many SENS proponents.

I find that SENS foundation (SENSF) is the only research body that I would consider both mature and progressive enough in the field, of engineering a solution to the problem of death, that I am forced to stand by it because I see no alternative except those who seem morbidly obsessed with the intricacies of death rather than those of life. Creating a separate institution somewhere in-between SENSF and the American Aging Association might be more funding friendly and attractive to more genuine scientists whilst still maintaining a life extension agenda, but too many institutions would be bad for solidarity.

I have to say that one reason that many keep coming back to is Aubrey de Grey as their reason for not thinking SENS is reasonable. Now, I am sure it is easier to put Aubrey de Grey as the leader of such a wave when invariably he attracts all sorts of characters to him who not only respect or admire him, but are looking at him to save them, in the same sort of way that many scientific intellectuals put their faith in the technological singularity. This view of Aubrey as a godhead should be propagated less by both sides as there are many scientists involved in SENS, some of which I have read plenty of high impact factor journal papers by, and no, I am not talking about Rejuvenation Research papers either. Aubrey de Grey I have seen is trying to counteract problems concerning his status at present by splitting the management of the SENSF to a number of people and referring newcomers to others instead of them asking him for answers and treating him as some sort of oracle. I am sure he also discourages linking himself to the wackier, crank characters that flock to him, instead trying to maintain more scientific networks; in just the same way that many gerontologists try to distance themselves from him. I must make it said that I feel awful writing about Aubrey as I think he has done a lot more than many scientists to capture the essence of what it is to be a scientist-to be at once intellectually responsible and an intellectual rebel.

Multiple distressing rumours concerning what without sarcasm or irony can be said to be dark maniacal schemes fit only for necromantic wizards that Aubrey and his scientific collaborators are involved in (and I am not talking about beard growing competitions) have been alluded. Can we blame the scientists spreading such rumours and hostilities? Conservative ageing scientists are scared that their already dwindling budget will be slashed further, but creating rumours about the things politicians and the public most fear will surely do no good to themselves. Concerning such rumour mongering I am sure the rest of the gerontological community would be happy to help slay the dragon they have created out of Aubrey by laying waste to any unfounded rumours at once.

As a final point I would like to list some pros of SENS to balance all the cons of such a risky endeavour: It encourages more theoretical biology, biotech innovation and interdisciplinary study. I find too much of molecular biology to be scripted and for nobody to really question how problems are being tackled. Other areas such as cancer research could learn a lot from the thought processes behind SENS, even if they are loath to think about WILT, which I do not blame them for.

Mindless screens of genes and proteins do not provoke or inspire innovation. It is only when someone says that, fundamentally, that they do not like what is going on, so lets go back to the drawing board and rethink the whole scenario that paradigm shifts (an overly misused phrase) occur.

Microarray analysis of senescent keratocytes (EK1.Br)

The study below carried out microarray analysis of senescent human fibroblastoid keratocytes (EK1.Br), which demonstrated that, in contrast with other fibroblast strains, senescence in this instance does not appear to be associated with a shift to a catabolic phenotype. The great thing about this paper is that it has provided a link to a fully searchable public access database, so you can explore the data yourself (www.madras.cf.ac.uk/cornea).

A transcriptomic analysis of the EK1.Br strain of human fibroblastoid keratocytes: The effects of growth, quiescence and senescence

David Kipling, Dawn L. Jones, S. Kaye Smith, Peter J. Giles, Katrin Jennert-Burston, Badr Ibrahim, Angela N.P. Sheerin, Amy J.C. Evans, William Rhys-Willams and Richard G.A. Faragher,

Abstract

There is a growing need within ocular research for well-defined cellular models of normal corneal biology. To meet this need we created and partially characterised a standard strain of human fibroblastoid keratocytes (EK1.Br) and demonstrated that phenotypic changes occur within these cells with replicative senescence in vitro. Using Affymetrix HG-U133A oligonucleotide arrays, this paper reports both a comprehensive analysis of the transcriptome of EK1.Br in the growing, quiescent and senescent states and a comparison of that transcriptome with those of primary corneal endothelium, lung fibroblasts and dermal fibroblasts grown under identical conditions. Data mining shows (i) that EK1.Br retain the characteristic transcriptional fingerprint of keratocytes in vitro (ii) that this phenotype can be distinguished from those of other ‘fibroblasts’ by groups of highly differentially expressed genes and (iii) that senescence induces a distinct dedifferentiation phenomenon in EK1.Br. These findings are contextualised into the broader literature on replicative senescence and are supported with a web-accessible and fully searchable public-access database.

www.madras.cf.ac.uk/cornea

Cellular senescence in pharmacogerontology research

The administration of pharmacological agents to older persons often results in a higher incidence of drug toxicity and adverse drug reactions compared with the young. This is mainly due to changes in pharmacokinetic (the process by which a drug is absorbed distributed, metabolised, and eliminated by the body) and pharmacodynamic (what a drug does to the body) properties believed to be the result of biological alterations linked to the ageing process. Therefore, understanding the mechanisms of ageing, the biological alterations they bring about and the biological consequence of such alterations could help answer questions concerning the pharmacokinetic and pharmacodynamic changes observed in the elderly.

The pharmacokinetic changes observed in elderly patients are well understood (click here) and allowances can be made for them. However, pharmacodynamic’s is much harder to predict as it requires an understanding of the biological changes associated with ageing (many of which may be individual specific). Insight into these processes has mainly been generated by laboratories focused on the molecular mechanism underlying the ageing process. These groups often have a limited understanding of the pharmacology of the elderly. Therefore, research in this area appears not to have progressed beyond cataloguing the observed drug responses in the elderly.

The accumulation of senescent cells in tissues has been linked to ageing and disease and as such could potentially alter the biological response to drugs in the elderly. When a cell becomes senescent, it undergoes a radically altered phenotype (click here). Microarray analysis of primary human lung fibroblasts (IMR-90) and primary skin fibroblasts (Detroit 551) reported that of the 4183 genes analysed, 165 were down-regulated and 191 up-regulated in senescent IMR-90 cells and 154 down-regulated and 76 up-regulated in senescent Detroit 551 cells compared with their growing counterparts (Chen et al 2004). This degree of alteration in the transcriptome is akin to that seen when cells are induced to differentiate (Truckenmiller et al 2001). Essentially, senescent cells should be treated as a completely different cell type from when they were growth competent. Therefore, more research should be carried to determine whether or not senescent cells display an altered responsiveness to pharmacological agents.

Conclusion

By bridging the gap between pharmacokinetic and pharmacodynamic studies and molecular gerontology it is hoped that pharmaceutical intervention might one day be more precisely targeted to the age of the patient (and thus, the biological status of the target tissue). It is anticipated that the development of in-vivo and in-vitro models of tissue ageing will facilitate the necessary advances in pharmacogerontology.

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See: Bridging the gap: ageing, pharmacokinetics and pharmacodynamics

Cellular senescence papers: different cell types

The following is a list of papers demonstrating cellular senescence in cell types other than fibroblasts. It will gradually be up-dated.

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Endothelial cells

Vascular endothelial senescence: from mechanisms to pathophysiology. Erusalimsky JD. J Appl Physiol. 2009 Jan;106(1):326-32. Epub 2008 Nov 26.

Telomere attrition and accumulation of senescent cells in cultured human endothelial cells. Hastings R, Qureshi M, Verma R, Lacy PS, Williams B. Cell Prolif. 2004 Aug;37(4):317-24

Endothelial Cell Senescence in Human Atherosclerosis. Minamino et al. Circulation. 2002;105:1541.)

A cell kinetic analysis of human umbilical vein endothelial cells. Kalashnik et al. Mech Ageing Dev. 2000 Dec 1;120(1-3):23-32.

Vascular smooth muscle cells

Vascular smooth muscle cells undergo telomere-based senescence in human atherosclerosis: effects of telomerase and oxidative stress. Matthews et al, Circ Res. 2006 Jul 21;99(2):156-64. Epub 2006 Jun 22

Microarray analysis of senescent vascular smooth muscle cells: A link to atherosclerosis and vascular calcification. Burton et al (2009) Experimental gerontology 2009 Oct;44(10):659-65 PubMed ID:(19631729)

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Replicative senescence of vascular smooth muscle cells enhances the calcification through initiating the osteoblastic transition. Nakano-Kurimoto et al,  Am J Physiol Heart Circ Physiol. 2009 Sep 11. [Epub ahead of print]

Epithelial cells

Beta-galactosidase histochemistry and telomere loss in senescent retinal pigment epithelial cells. Matsunaga et al, Invest Ophthalmol Vis Sci. 1999 Jan;40(1):197-202

T-cells

T cell replicative senescence: pleiotropic effects on human aging. Effros RB, Ann N Y Acad Sci. 2004 Jun;1019:123-6

The role of CD8+ T-cell replicative senescence in human aging. Effros RB, Dagarag M, Spaulding C, Man J. Immunol Rev. 2005 Jun;205:147-57

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Microglia

Microglial senescence: does the brain's immune system have an expiration date? Streit WJ Trends Neurosci. 2006 Sep;29(9):506-10. Epub 2006 Jul 20

The role of microglial cellular senescence in the aging and Alzheimer diseased brain. Flanary B, Rejuvenation Res. 2005 Summer;8(2):82-5

Astrocytes

Astrocytes aged in vitro show a decreased neuroprotective capacity. Pertusa et al, J Neurochem. 2007 May;101(3):794-805. Epub 2007 Jan 23

Osteoblasts

Demonstration of cellular aging and senescence in serially passaged long-term cultures of human trabecular osteoblasts. Kassem et al. Osteoporos Int. 1997;7(6):514-24.

Relationship between periarticular osteoporosis and osteoblast senescence in patients with rheumatoid arthritis. Yudoh K, Matsuno H, Kimura T., Clin Calcium. 2001 May;11(5):612-8

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Chondrocytes

Aging, articular cartilage chondrocyte senescence and osteoarthritis. Martin and Buckwalter, Biogerontology. 2002;3(5):257-64

Pancreatic Beta cells

Pancreatic beta cell senescence contributes to the pathogenesis of type 2 diabetes in high-fat diet-induced diabetic mice. Sone H, Kagawa Y., Diabetologia. 2005 Jan;48(1):58-67. Epub 2004 Dec 29

Hepatocytes

Role of replicative senescence in the progression of fibrosis in hepatitis C virus (HCV) recurrence after liver transplantation. Trak-Smayra et al, Transplantation. 2004 Jun 15;77(11):1755-60

Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis. Wiemann et al, FASEB J. 2002 Jul;16(9):935-42

Renal cells

Increased expression of senescence-associated cell cycle inhibitor p16INK4a in deteriorating renal transplants and diseased native kidney. Melk et al, Am J Transplant. 2005 Jun;5(6):1375-82

Stem/Progenitor cells

Replicative senescence of mesenchymal stem cells: a continuous and organized process. Wagner et al, PLoS ONE. 2008 May 21;3(5):e2213

Premature senescence of highly proliferative endothelial progenitor cells is induced by tumor necrosis factor-alpha via the p38 mitogen-activated protein kinase pathway. Zhang et al, FASEB J. 2009 May;23(5):1358-65. Epub 2009 Jan 5

DISEASE FOCUS: Alzheimer’s

Introduction

Alzheimer’s disease (AD) is the most common form of dementia and is found predominantly in people aged over 65 years. It is progressive, degenerative and currently irreversible. Features of the disease include memory loss, decreased reasoning and judgment and changes in mood, behaviour and personality. The majority of the research into AD is focused on protein plaques (mostly made up of a protein called B-amyloid) and neurofibrillary tangles (composed of a protein called tau) found in the brain of AD patients. The role of amyloid plaques and neurofibrillary tangles on the functioning of the brain is poorly understood and research is ongoing. This article however, neither focuses on plaques or tangles, but instead on the role of cellular senescence (specifically microglial and astrocytes) in the development and/or progression of AD.

Microglial cells and Astrocytes in Alzheimer’s

Both microglial and astrocytes are mitotic cells which have been shown to undergo cellular senescence (Streit, 2006 and Pertusa et al, 2007). Moving around the brain, microglia function as immune cells to remove damaged neurons, plaques and infecting micro-organisms (Pivneva, 2008). Astrocytes appear to have numerous responsibilities including providing nutrients to neurons and neuronal maintenance (Seth and Koul, 2008, Rodriguez et al 2009). Therefore, without microglia and astrocytes, or a decline in their function, there would most likely be an increase in neuronal damage and this could manifest as disease. An accumulation of senescent microglial and astrocytes in the brain could lead to such a functional decline. However, as with a number of cell types, little is known about the senescent-specific phenotype of microglia and astrocytes and little work has been carried out to investigate the possible contribution senescent cells may have on the development/progression of AD.

An interesting study by Streit et al (2007) demonstrated that the presence of amyloid protein promotes cellular senescence in microglial cells. Amyloid protein causes microglial cells to become activated and thus proliferate to facilitate amyloid removal. Constant activation and cell turnover of microglial cells would result in gradual telomere attrition and thus an increased appearance of senescent cells. Apolipoprotein E (apoE) also plays a role in the degradation and clearance of amyloid protein by astrocytes. However, varients of this gene have been shown to be a major risk factor in the development of late onset AD (Wang and Ding, 2008). Research has shown that this varient enhances the production of amyloid protein (Ye et al, 2005), which may consequently lead to an increase in microglial activation and accelerated appearance of senescent microglia. The presence of amyloid is just one example of how microglial cell senescence may become accelerated, but other currently unknown risk factors may also have the same impact.

Little is known about the mechanisms by which astrocytes become activated and it can only be speculated as to the effects senescent astrocytes would have on the brain (if any). Astrocytes have been shown to become activated and proliferate in culture in the presence of cytokines and growth factors (Selmaj et al 1990) and by neuroinflammation in the brain (Norris et al, 2005). General features of a senescent phenotype appear to be an up-regulation of pro-inflammatory cytokines, growth factors and matrix degrading proteins. If this is true for senescent microglial cells, then it could be speculated that the accumulation of senescent microglial cells (if they persist in tissue) may consequently lead to the activation and proliferation of astrocytes. Interestingly, interleukin 1 (a cytokine known to stimulate astrocyte proliferation) is elevated in both Down syndrome (risk factor for AD) and in AD (Griffin et al, 1989). This up-regulation of interleukin 1 appears to orinate from activated microglial (Mrak, 2001). Inflammaotory mediators have long been shown to be up-regulated in pathologically vulnerable regions of the brain in AD (Rogers, 2008). The constant proliferation of astrocytes would eventially result in the accumulated appearance of senescent astrocytes (further research needs to be carried out to determine if astrocyte numbers increase in AD progression). This means that neurons will become functionally impaired, damaged or lossed. Pertusa et al (2007) found that aged astrocytes in vitro show a decreased neuroprotective cacpacity. Long-term cultures of astrocytes demonstrated positive staining for senescence-associated-beta-galactosidase (a senescent marker, Dimri et al, 1995) suggesting that this functional decline is associated with the senescent phenotype of astrocytes.

Neuronal loss may not be a major problem initally since they are most likey replaced by neural stem/progenitor cells (Taupin, 2006). However, these cells have also been shown to undergo cellular senescence or become functionally impaired with age (Sharpless and DePinho 2007, Ruzankina and Brown 2007). This means, the brain would reach a point where neurons are being lost without replacement.

A theoretical consequence of the senescent astrocyte phenotype might be related to that which is observed in senescent vascular endothelial cells (ECs). Senescent vascular ECs show a reduction in nitric oxide (NO) production by eNOS (Minamino et al, 2002). In the vascular system, NO signals the surrounding smooth muscle to relax, thus resulting in vasodilation and increasing blood flow. A reduction in NO would therefore restrict bloodflow and reduce oxygen supply to much needed tissues. NO reduction has been suggested to be a significant risk factor for cardiovascular disease.

Astrocytes perform many functions, including biochemical support of endothelial cells which form the blood-brain barrier. eNOS activity has also been shown to be present in astrocytes (Lin et al, 2007), but the impact of cellular senescence (if any) on eNOS activity on this cell type is currently lacking. However, since it has been shown that astrocytes play a direct role in controlling blood flow in the brain (Koehler et al 2009) and if senescent astrocytes do reduce the synthesis of NO, then this may lead to a reduction of blood flow to certain areas of the brain. This means less oxygen and potential cell death..

One final point of mention. In AD, the hippocampus (important in long-term memory) and the neocortex (higher level cognitive function such as language, learning and memory) are one of the first areas of the brain to undergo damage (Scheff and Price, 2006). Interestingly, both microglial and astrocytes have been shown to specifically proliferate in the hippocampus and temporal neocortex following global cerebral ischemia in young adult monkey brain (Tonchev et al, 2003). This region specific proliferation of microglial cells and astrocytes, the same region affected in AD, provides some link that these two cell types may play a role in the pathogenesis of AD.

Conclusion

To date little work has been carried out to investigate microglial cell and astrocyte senescence in AD. Little is known about the senescent phenotype of microglial cells and astrocytes and what impact (if any) this phenotype may consequently have on the brain. A number of points in this article can only be speculative, but based on what we know about the phenotype of other senescent cell types and the theoretical impact of their presence, it is not difficult to envisage a role for cellular senescence in AD development and/or progression.

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ALSO SEE:

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Phenotypic changes associated with cellular senescence

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DISEASE FOCUS: Atherosclerosis and vascular calcification
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Cellular senescence in disease states

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Cellular senescence, ageing and disease (2009)

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