The purpose of the SENS conference series, like all the SENS initiatives, is to expedite the development of truly effective therapies to postpone and treat human aging by tackling it as an engineering problem: not seeking elusive and probably illusory magic bullets, but instead enumerating the accumulating molecular and cellular changes that eventually kill us and identifying ways to repair - to reverse - those changes, rather than merely to slow down their further accumulation. This broadly defined regenerative medicine - which includes the repair of living cells and extracellular material in situ - applied to damage of aging, is what we refer to as rejuvenation biotechnologies.
Here are selection of abstracts from the SENS 6 conference.
Engineering stem cells for liver and gut regeneration
Marrow stromal cells (MSC) have several unique properties, which make them well suited both for regenerative medicine and gene delivery. These include the ease of isolation and the ability to be considerably expanded in culture without losing engraftment capacity. Furthermore, MSC have been reported to reduce local inflammation, blunt immune response, and counteract the chemotactic signals released to recruit immune cells to the site of injury/inflammation.
Nevertheless, controversy still remains whether these cells, upon transplantation, would be able to be recognized in an allogeneic setting, lessening their therapeutic potential when compared with their autologous counterpart. Since MSC express negligible amounts of HLA-II, but display variable levels of HLA-I on their surface, and harbor several ligands to activating NK cell receptors, it is likely that MSC can become a target of NK and CTL. We genetically engineered MSC to express the HCMV proteins US2, US3, US6, and US11, since they were shown to reduce HLA-I surface levels on somatic cells. Moreover, this reduction in HLA-I levels prevented CTL recognition thereby preventing activation and killing of infected cells during a normal HCMV infection.
In conclusion, we are able to genetically engineer MSC to have an enhanced survival advantage in the presence of an exacerbated inflammatory microenvironment and/or in an allogeneic transplantation setting, as a result of decreased rejection by the immune system. This should extend their survival time and thereby enhance their therapeutic potential.
Vascular ageing: causes, mechanisms, complications and possible therapeutic strategies
Ageing is increasingly considered as an independent factor for the development of cardiovascular diseases (CDs). During ageing, there are structural and functional changes in the vasculature, including dilated lumen, altered intimal-medial thickness, vascular stiffness, endothelial dysfunction, increased endothelial apoptosis, matrix metalloproteinase dysregulation, increased expression of inflammatory molecules, aggravated oxidative stress and shortened telomere length. These changes leave the body and the arteries more susceptible to hypertension, atherosclerosis, medial degeneration and the onset of a different array of artery complications (i.e. myocardial infarction, stroke, aneurysms). Metabolic syndrome, obesity and diabetes are known to accelerate ageing process and, particularly, vascular ageing. In this presentation, most of these aspects will be described in the light of recent literature data and giving particular emphasis on those, which represent object of our studies. In particular, the data discussed in this report will be based on an expert opinion derived on the findings from author studies on ageing, age-related diseases and inflammation. On the other hand, our interest will be focused in proving potential working hypotheses about possible targets for the development of strategies both for prevention and improvement of the quality of life in elderly population.
Accelerating translational research processes from bench to clinic
The productivity of medical innovation has been in decline, and this threatens the commitment of both public and private funders. However, there are both disruptive technologies and disruptive ideas that promise a turnaround. CASMI (www.casmi.org.uk) is exploring both, and developing testable models for change - including new open innovation-based discovery models, adaptive licensing of medicines, the use of real world data in development, and the personalisation of therapy on both genomic and behavioural grounds. With the support of SENS, CASMI is also investigating the translational issues facing cell therapy, so that the highly promising science delivers patient benefit as speedily and affordably as possible.
Treating age-related macular degeneration through enhanced lysosomal degradation of A2E
Age Related Macular Degeneration (AMD) is the leading cause of visual loss among people 65 years and older. This disease manifests into two distinct forms, wet and dry. The pathogenesis for both forms is poorly understood and numerous hypothetical models have been studied to better understand their mechanism. The dry form of AMD involves atrophy of the retinal pigment epithelium (RPE) by the accumulation of bisretinoid lipofuscin within lysosomes as the cells phagocytose the outer membranes of the photoreceptors. A major fluorescent component of RPE lipofuscin is a compound known as pyridinum bisretinoid (A2E). We have been able to degrade A2E by exogenous enzyme delivery to cultured human RPE cells and cell free systems. We have discovered an enzyme (SENS20) that, in the presence of its co-substrate, has the ability to degrade A2E in a dose-dependent manner without damaging RPE cells. This dose-dependency is evident in vitro and in cell culture assays. Our studies show evidence for SENS20’s positive enzymatic activity towards synthetic A2E cultured with human RPE cells and its ability for potential treatment of dry AMD.
Hypothalamic control of aging and longevity
The hypothalamus is a converging point that integrates metabolic, neural, neuroendocrine, and neuroimmune signals to affect the whole body physiology. The long-standing research interest of my research is to investigate the role of neural dysregulations, in particular in terms of neural inflammation in the development of aging and aging-related diseases. Our recent observations demonstrated that the hypothalamus contains adult neural stem cells, and IKK/NF-kB activation affects the fate of these cells and cause disease consequences in relation with aging and metabolic syndrome. Taken together, we have established several conceptual models addressing the central mechanism of aging, and identified the involved mechanism that is mediated by integrated actions of neural, neuroendocrine and immune systems. We also have generated strategies for combating aging-related diseases through targeting the neural inflammatory molecular pathways. Several highlights of our recent research activities will be discussed in this symposium.
Sequencing the genome of the longest-lived mammal to identify longevity assurance mechanisms
The bowhead whale (Balaena mysticetus) has not only been estimated to live over 200 years, making it the longest-lived mammal, but these animals remain disease-free until much more advanced ages than humans can. The mechanisms for the longevity and resistance to aging-related diseases of bowhead whales are unknown, but it is clear they must possess aging prevention mechanisms. In particular in the context of cancer, bowhead whales must have anti-tumour mechanisms, because given their large size and longevity their cells must have a massively lower chance of developing into cancer when compared to human cells. In this project, we are sequencing and analyzing the genome of the bowhead whale to identify longevity assurance mechanisms. We are also performing analyses to identify promising candidate genes for further study and identify possible mechanisms that may explain the long lifespan and resistance to age-related diseases of bowhead whales. Overall, this project will provide a key resource for studying the bowhead whale’s exceptional longevity and resistance to diseases. Studying a species so long-lived and with such an extraordinary resistance to age-related diseases will help elucidate mechanisms and genes conferring longevity and disease resistance in mammals that in the future may be applied to improve human health.
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