Vascular Sphincter and Microangioarchitecture in the Central Nervous System: Constriction of Intraparenchymal Blood Vessels Following a Treatment of Vasoconstrictive Neurotransmitter

The site of action of neuropeptide Y (NPY), a potent vasoconstrictive neurotransmitter, on the intraparenchymal blood vessels in the rat parietal cortex was demonstrated using a corrosion cast technique with scanning electron microscopy. Our observations were confined to the cortical area where the regional cerebral blood flow (rCBF) had been reduced significantly by in situ application of NPY. A striking finding in that area was the diffuse narrowing of the perforating arteries in the upper cortical layers. Ring-like compressions on the corrosion casts, presumably formed by active vascular sphincters along the arteries, capillaries and venules within the brain parenchyma, seemed to be more prominent in the perforating arteries of the NPY-treated cortex as compared with those of control cortex. We conclude that NPY-containing nerve fibers along the parenchymal blood vessels may take part in regulating the rCBF primarily by reducing the caliber of the proximal perforating arteries

A Study of the PDGF Signaling Pathway with PRISM

In this paper, we apply the probabilistic model checker PRISM to the analysis of a biological system -- the Platelet-Derived Growth Factor (PDGF) signaling pathway, demonstrating in detail how this pathway can be analyzed in PRISM. We show that quantitative verification can yield a better understanding of the PDGF signaling pathway.Comment: In Proceedings CompMod 2011, arXiv:1109.104

Serum amyloid A primes microglia for ATP-dependent interleukin-1\u3b2 release

Acute-phase response is a systemic reaction to environmental/inflammatory insults and involves production of acute-phase proteins, including serum amyloid A (SAA). Interleukin-1\u3b2 (IL-1\u3b2), a master regulator of neuroinflammation produced by activated inflammatory cells of the myeloid lineage, in particular microglia, plays a key role in the pathogenesis of acute and chronic diseases of the peripheral nervous system and CNS. IL-1\u3b2 release is promoted by ATP acting at the purinergic P2X7 receptor (P2X7R) in cells primed with toll-like receptor (TLR) ligands

Current Bioengineering and Regenerative Strategies for the Generation of Kidney Grafts on Demand

[EN] Currently in the USA, one name is added to the organ transplant waiting list every 15 min. As this list grows rapidly, fewer than one-third of waiting patients can receive matched organs from donors. Unfortunately, many patients who require a transplant have to wait for long periods of time, and many of them die before receiving the desired organ. In the USA alone, over 100,000 patients are waiting for a kidney transplant. However, it is a problem that affects around 6% of the word population. Therefore, seeking alternative solutions to this problem is an urgent work. Here, we review the current promising regenerative technologies for kidney function replacement. Despite many approaches being applied in the different ways outlined in this work, obtaining an organ capable of performing complex functions such as osmoregulation, excretion or hormone synthesis is still a long-term goal. However, in the future, the efforts in these areas may eliminate the long waiting list for kidney transplants, providing a definitive solution for patients with end-stage renal disease.This study was supported by a grant from ALCER-TURIA, ASTELLAS and PRECIPITA CROWDFUNDING.Garcia-Dominguez, X.; Vicente Antón, JS.; Vera Donoso, CD.; Marco-Jiménez, F. (2017). Current Bioengineering and Regenerative Strategies for the Generation of Kidney Grafts on Demand. Current Urology Reports. 18(1):1-8. https://doi.org/10.1007/s11934-017-0650-6S18181Ott HC, Mathisen DJ. Bioartificial tissues and organs: are we ready to translate? Lancet. 2011;378:1977–8.Salvatori M, Peloso A, Katari R, Orlando G. Regeneration and bioengineering of the kidney: current status and future challenges. Curr Urol Rep. 2014;15:379.D’Agati VD. Growing new kidneys from embryonic cell suspensions: fantasy or reality? J Am Soc Nephrol. 2002;11:1763–6.Abouna GM. Organ shortage crisis: problems and possible solutions. 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J Biol Chem. 2014;289:4594–9.Freedman BS, Brooks CR, Lam AQ, Fu H, Morizane R, Agrawal V, et al. Modelling kidney disease with CRISPR-mutant kidney organoids derived from human pluripotent epiblast spheroids. Nat Commun. 2015;6:8715.Hu J, Lei Y, Wong WK, Liu S, Lee KC, He X, et al. Direct activation of human and mouse Oct4 genes using engineered TALE and Cas9 transcription factors. Nucleic Acids Res. 2014;42:4375–90.Den Hartogh SC, Schreurs C, Monshouwer-Kloots JJ, Davis RP, Elliott DA, Mummery CL, et al. Dual reporter MESP1 mCherry/w-NKX2-5 eGFP/w hESCs enable studying early human cardiac differentiation. Stem Cells. 2015;33:56–67.Fukui A, Yokoo T. Kidney regeneration using developing xenoembryo. Curr Opin Organ Transplant. 2015;20:160–4.Chen J, Lansford R, Stewart V, Young F, Alt FW. RAG-2-deficient blastocyst complementation: an assay of gene function in lymphocyte development. Proc Natl Acad Sci U S A. 1993;90:4528–32.Ueno H, Turnbull BB, Weissman IL. Two-step oligoclonal development of male germ cells. Proc Natl Acad Sci U S A. 2009;106:175–80.Fraidenraich D, Stillwell E, Romero E, Wilkes D, Manova K, Basson CT, et al. Rescue of cardiac defects in id knockout embryos by injection of embryonic stem cells. Science. 2004;306:247–52.Kobayashi T, Yamaguchi T, Hamanaka S, Kato-Itoh M, Yamazaki Y, Ibata M, et al. Generation of rat pancreas in mouse by interspecific blastocyst injection of pluripotent stem cells. Cell. 2010;142:787–99.Matsunari H, Nagashima H, Watanabe M, Umeyama K, Nakano K, Nagaya M, et al. Blastocyst complementation generates exogenic pancreas in vivo in apancreatic cloned pigs. Proc Natl Acad Sci U S A. 2013;110:4557–62.Espejel S, Roll GR, McLaughlin KJ, Lee AY, Zhang JY, Laird DJ, et al. Induced pluripotent stem cell-derived hepatocytes have the functional and proliferative capabilities needed for liver regeneration in mice. J Clin Invest. 2010;120:3120–6.Usui J, Kobayashi T, Yamaguchi T, Knisely AS, Nishinakamura R, Nakauchi H. Generation of kidney from pluripotent stem cells via blastocyst complementation. Am J Pathol. 2012;180:2417–26.Aggarwal S, Moggio A, Bussolati B. Concise review: stem/progenitor cells for renal tissue repair: current knowledge and perspectives. Stem Cells Transl Med. 2013;2:1011–9.Yokote S, Yokoo T. Organogenesis for kidney regeneration. Curr Opin Organ Transplant. 2013;18:186–90.Crapo PM, Gilbert TW, Badylak SF. An overview of tissue and whole organ decellularization processes. Biomaterials. 2011;32:3233–43.Berthiaume F, Maguire TJ, Yarmush ML. Tissue engineering and regenerative medicine: history, progress, and challenges. Annu Rev Chem Biomol Eng. 2011;2:403–30.Badylak SF. Xenogeneic extracellular matrix as a scaffold for tissue reconstruction. Transpl Immunol. 2004;12:367–77.Badylak SF. The extracellular matrix as a biologic scaffold material. Biomaterials. 2007;28:3587–93.Ott HC, Matthiesen TS, Goh SK, Black LD, Kren SM, Netoff TI, et al. Perfusion-decellularized matrix: using nature’s platform to engineer a bioartificial heart. Nat Med. 2008;14:213–21.Yokoo T. Kidney regeneration with stem cells: an overview. Nephron Exp Nephrol. 2014;126(2):54.Uygun BE, Soto-Gutierrez A, Yagi H, Izamis ML, Guzzardi MA, Shulman C, et al. Organ reengineering through development of a transplantable recellularized liver graft using decellularized liver matrix. Nat Med. 2010;16:814–20.Ott HC, Clippinger B, Conrad C, Schuetz C, Pomerantseva I, Ikonomou L, et al. Regeneration and orthotopic transplantation of a bioartificial lung. Nat Med. 2010;16:927–33.Montserrat N, Garreta E, Izpisua Belmonte JC. Regenerative strategies for kidney engineering. FEBS J. 2016. doi: 10.1111/febs.13704 .Murphy SV, Atala A. 3D bioprinting of tissues and organs. Nat Biotechnol. 2014;32:773–85.Groll J, Boland T, Blunk T, Burdick JA, Cho DW, Dalton PD, et al. Biofabrication: reappraising the definition of an evolving field. Biofabrication. 2016;8:013001.Mandrycky C, Wang Z, Kim K, Kim DH. 3D bioprinting for engineering complex tissues. Biotechnol Adv. 2016;34:422–34.Uzarski JS, Xia Y, Belmonte JC, Wertheim JA. New strategies in kidney regeneration and tissue engineering. Curr Opin Nephrol Hypertens. 2014;23:399–405.Humes HD, Buffington DA, MacKay SM, Funke AJ, Weitzel WF. Replacement of renal function in uremic animals with a tissue-engineered kidney. Nat Biotechnol. 1999;17:451–5.Chevtchik NV, Fedecostante M, Jansen J, Mihajlovic M, Wilmer M, Rüth M, Masereeuw R, Stamatialis D. Upscaling of a living membrane for bioartificial kidney device. Eur J Pharmacol. 2016.Humes HD, Sobota JT, Ding F, Song JH. A selective cytopheretic inhibitory device to treat the immunological dysregulation of acute and chronic renal failure. Blood Purif. 2010;29:183–90.Tumlin J, Wali R, Williams W, Murray P, Tolwani AJ, Vinnikova AK, et al. Efficacy and safety of renal tubule cell therapy for acute renal failure. J Am Soc Nephrol. 2008;19:1034–40.Yokoo T, Ohashi T, Shen JS, Sakurai K, Miyazaki Y, Utsunomiya Y, et al. Human mesenchymal stem cells in rodent whole-embryo culture are reprogrammed to contribute to kidney tissues. Proc Natl Acad Sci U S A. 2005;102(9):3296–300.Yokoo T, Fukui A, Ohashi T, Miyazaki Y, Utsunomiya Y, Kawamura T, et al. Xenobiotic kidney organogenesis from human mesenchymal stem cells using a growing rodent embryo. J Am Soc Nephrol. 2006;17:1026–34.Cooper DK. A brief history of cross-species organ transplantation. Proc (Bayl Univ Med Cent). 2012;25:49–57.Costa MR, Fischer N, Gulich B, Tönjes RR. Comparison of porcine endogenous retroviruses infectious potential in supernatants of producer cells and in cocultures. Xenotransplantation. 2014;21:162–73.Takeda S, Rogers SA, Hammerman MR. Differential origin for endothelial and mesangial cells after transplantation of pig fetal renal primordia into rats. Transpl Immunol. 2006;15:211–5.Yasutomi Y. Establishment of specific pathogen-free macaque colonies in Tsukuba Primate Research Center of Japan for AIDS research. Vaccine. 2010;28:75–7.Dekel B, Burakova T, Arditti FD, Reich-Zeliger S, Milstein O, Aviel-Ronen S, et al. Human and porcine early kidney precursors as a new source for transplantation. Nat Med. 2003;9:53–60.Hammerman MR. Classic and current opinion in embryonic organ transplantation. Curr Opin Organ Transplant. 2014;19:133–9.Rogers SA, Hammerman MR. Prolongation of life in anephric rats following de novo renal organogenesis. Organogenesis. 2004;1:22–5.•• Yokote S, Matsunari H, Iwai S, Yamanaka S, Uchikura A, Fujimoto E, et al. Urine excretion strategy for stem cell-generated embryonic kidneys. Proc Natl Acad Sci U S A. 2015;112:12980–5. This manuscript describes the developed-metanephros ability to produce urine when it was connected to the excretory system of the recipient organism. They demonstrated the potential of this technique as a possible solution to the kidneys shortage.Yokote S, Yokoo T, Matsumoto K, Utsunomiya Y, Kawamura T, Hosoya T. The effect of metanephroi transplantation on blood pressure in anephric rats with induced acute hypotension. Nephrol Dial Transplant. 2012;27:3449–55.Matsumoto K, Yokoo T, Yokote S, Utsunomiya Y, Ohashi T, Hosoya T. Functional development of a transplanted embryonic kidney: effect of transplantation site. J Nephrol. 2012;25:50–5.Yokote S, Yokoo T, Matsumoto K, Ohkido I, Utsunomiya Y, Kawamura T, et al. Metanephroi transplantation inhibits the progression of vascular calcification in rats with adenine-induced renal failure. Nephron Exp Nephrol. 2012;120:e32–40.Matsumoto K, Yokoo T, Matsunari H, Iwai S, Yokote S, Teratani T, et al. Xeno‐transplanted embryonic kidney provides a niche for endogenous mesenchymal stem cell differentiation into erythropoietin-producing tissue. Stem Cells. 2012;30:1228–35.Abrahamson DR. Glomerular development in intraocular and intrarenal graft of fetal kidney. Lab Investig. 1991;64:629–39.Woolf AS, Palmer SJ, Snow ML, Fine LG. Creation of functioning chimeric mammalian kidney. Kidney Int. 1990;38:991–7.Robert B, St John PL, Hyink DP, Abrahamson DR. Evidence that embryonic kidney cells expressing flk-1 are intrinsic, vasculogenic angioblasts. Am J Physiol. 1996;271:F744–53.Koseki C, Herzlinger D, Al-Awqati Q. Integration of embryonic nephrogenic cells carrying a reporter gene into functioning nephrons. Am J Physiol. 1991;261:C550–4.Rogers SA, Lowell JA, Hammerman NA, Hammerman MR. Transplantation of developing metanephroi into adult rats. Kidney Int. 1998;54:27–37.Barakat TL, Harrison RG. The capacity of fetal and neonatal renal tissues to regenerate and differentiate in a heterotropic allogenic subcutaneous tissue site in the rat. J Anat. 1971;110:393–407.Rogers SA, Liapis H, Hammerman MR. Transplantation of metanephroi across the major histocompatibility complex in rats. Am J Physiol Regul Integr Comp Physiol. 2001;280:R132–6.Vera-Donoso CD, García-Dominguez X, Jiménez-Trigos E, García-Valero L, Vicente JS, Marco-Jiménez F. Laparoscopic transplantation of metanephroi: a first step to kidney xenotransplantation. Actas Urol Esp. 2015;39:527–34.•• Marco-Jiménez F, Garcia-Dominguez X, Jimenez-Trigos E, Vera-Donoso CD, Vicente JS. Vitrification of kidney precursors as a new source for organ transplantation. Cryobiology. 2015;70:278–82. This study found that it is possible to create a long-term biobank of kidney precursors as an unlimited source of organs for transplantation and open new therapeutic possibilities for the patients with chronic renal failure.Garcia-Dominguez X, Vicente JS, Vera-Donoso C, Jimenez-Trigos E, Marco-Jiménez F. First steps towards organ banks: vitrification of renal primordia. CryoLetters. 2016;37:47–52.•• García-Domínguez X, Vera-Donoso CD, García-Valero L, Vicente JS, Marco-Jiménez F. Embryonic organ transplantation: the new era of xenotransplantation. In: Abdeldayem H, El-Kased AF, El-Shaarawy A, editors. Frontiers in transplantology. 2016. pp. 26–46. This manuscript describes for the first time the protocol for transplantation of embryonic kidneys as an organ replacement therapy using laparoscopic surgery.Bottomley MJ, Baicu S, Boggs JM, Marshall DP, Clancy M, Brockbank KG, et al. Preservation of embryonic kidneys for transplantation. Transplant Proc. 2005;37:280–4.Hara J, Tottori J, Anders M, Dadhwal S, Asuri P, Mobed-Miremadi M. Trehalose effectiveness as a cryoprotectant in 2D and 3D cell cultures of human embryonic kidney cells. Artif Cells Nanomed Biotechnol. 2016. doi: 10.3109/21691401.2016.1167698 .Xu Y, Zhao G, Zhou X, Ding W, Shu Z, Gao D. Biotransport and intracellular ice formation phenomena in freezing human embryonic kidney cells (HEK293T). Cryobiology. 2014;68:294–302

Early immune pressure initiated by tissue-resident memory T cells sculpts tumor evolution in non-small cell lung cancer

Tissue-resident memory T (TRM) cells provide immune defense against local infection and can inhibit cancer progression. However, it is unclear to what extent chronic inflammation impacts TRM activation and whether TRM cells existing in tissues before tumor onset influence cancer evolution in humans. We performed deep profiling of healthy lungs and lung cancers in never-smokers (NSs) and ever-smokers (ESs), finding evidence of enhanced immunosurveillance by cells with a TRM-like phenotype in ES lungs. In preclinical models, tumor-specific or bystander TRM-like cells present prior to tumor onset boosted immune cell recruitment, causing tumor immune evasion through loss of MHC class I protein expression and resistance to immune checkpoint inhibitors. In humans, only tumors arising in ES patients underwent clonal immune evasion, unrelated to tobacco-associated mutagenic signatures or oncogenic drivers. These data demonstrate that enhanced TRM-like activity prior to tumor development shapes the evolution of tumor immunogenicity and can impact immunotherapy outcomes

The selective peroxisome proliferator-activated receptor alpha modulator (SPPARM) paradigm : conceptual framework and therapeutic potential: A consensus statement from the International Atherosclerosis Society (IAS) and the Residual Risk Reduction Initiative (R3i) Foundation

In the era of precision medicine, treatments that target specific modifiable characteristics of high-risk patients have the potential to lower further the residual risk of atherosclerotic cardiovascular events. Correction of atherogenic dyslipidemia, however, remains a major unmet clinical need. Elevated plasma triglycerides, with or without low levels of high-density lipoprotein cholesterol (HDL-C), offer a key modifiable component of this common dyslipidemia, especially in insulin resistant conditions such as type 2 diabetes mellitus. The development of selective peroxisome proliferator-activated receptor alpha modulators (SPPARM) offers an approach to address this treatment gap. This Joint Consensus Panel appraised evidence for the first SPPARM agonist and concluded that this agent represents a novel therapeutic class, distinct from fibrates, based on pharmacological activity, and, importantly, a safe hepatic and renal profile. The ongoing PROMINENT cardiovascular outcomes trial is testing in 10,000 patients with type 2 diabetes mellitus, elevated triglycerides, and low levels of HDL-C whether treatment with this SPPARM agonist safely reduces residual cardiovascular risk.Peer reviewe

Residual vascular risk in diabetes – will the SPPARM alpha concept hold the key?

No abstract available

From old organisms to new molecules: integrative biology and therapeutic targets in accelerated human ageing

Understanding the basic biology of human ageing is a key milestone in attempting to ameliorate the deleterious consequences of old age. This is an urgent research priority given the global demographic shift towards an ageing population. Although some molecular pathways that have been proposed to contribute to ageing have been discovered using classical biochemistry and genetics, the complex, polygenic and stochastic nature of ageing is such that the process as a whole is not immediately amenable to biochemical analysis. Thus, attempts have been made to elucidate the causes of monogenic progeroid disorders that recapitulate some, if not all, features of normal ageing in the hope that this may contribute to our understanding of normal human ageing. Two canonical progeroid disorders are Werner’s syndrome and Hutchinson-Gilford progeroid syndrome (also known as progeria). Because such disorders are essentially phenocopies of ageing, rather than ageing itself, advances made in understanding their pathogenesis must always be contextualised within theories proposed to help explain how the normal process operates. One such possible ageing mechanism is described by the cell senescence hypothesis of ageing. Here, we discuss this hypothesis and demonstrate that it provides a plausible explanation for many of the ageing phenotypes seen in Werner’s syndrome and Hutchinson-Gilford progeriod syndrome. The recent exciting advances made in potential therapies for these two syndromes are also reviewed