Cell Reprogramming Leaps Ahead: First Transplant of Primate Induced Pluripotent Cell-Derived Neurons into Donor BrainPosted by Michael Rae on April 17, 2013 | Chief Science Officer's Team
The preliminary results of a clinical trial for a disease of "premature aging" are hopeful and inspiring, though they cannot directly inform the development of rejuvenation biotechnologies.
Aging laboratory rodents are the foundation of our ability to study the degenerative aging process, and develop the rejuvenation biotechnologies that will arrest and reverse it. They're also expensive, logistically intensive, and in short supply. A new UK initiative has been establish to greatly expand what we can learn from the aging animals in our collective care, and to get a fuller picture of aging and its deceleration and reversal than has hitherto been possible.
Recent studies show the potential -- and the limits -- of inducing telomerase expression in aging mice. We place these results in context and explore their implications for new treatments targeting age-related degeneration in humans.
SENS Foundation-funded research shows that expression of a modified microbial enzyme protects human cells against 7-ketocholesterol toxicity, advancing research toward remediation of the foam cell and rejuvenation of the atherosclerotic artery.
UCLA Researchers have exploited a recently-discovered mammalian system for the mitochondrial import of nuclear-encoded RNA to import, express, and demonstrate functional protein translation from engineered mRNA and tRNA constructs. They used this system, with modifications for mitochondrial targeting and orthotopic translation, to rescue respiration in human mitochondriopathy cells. While further characterization and extension is clearly needed, this approach appears offer great promise for the correction of age-related mitochondrial DNA mutations.
Immunotherapy targeting the age-related accumulation of extracellular aggregates, in the form of ß-amyloid, is the first rejuvenation biotechnology to reach Phase III human clinical trials.
With True Cells Come True Benefits: the Potential of Human Pluripotent Stem Cells Released in a Model of Parkinson's DiseasePosted by Michael Rae on November 24, 2011 | Chief Science Officer's Team
"Senescent" cells progressively restrict the body's capacity for tissue renewal and secrete factors that disrupt local tissue homeostasis. A new study provides proof-of-concept that ablation of these cells can delay -- and potentially contribute to the reversal of -- age-related tissue dysfunction and disease.
Accumulation of soluble and insoluble aggregates of beta-amyloid protein (Aß) and other malformed proteins accumulate in brain aging and neurodegenerative disease, leading progressively to neuronal dysfunction and/or loss.
To develop an unbreachable defense against cancer, SENS Foundation is pursuing the WILT (Wholebody Interdiction of Lengthening of Telomeres, or OncoSENS) strategy of preemptively deleting genes essential to the cellular telomere-maintenance mechanisms (TMM) from all somatic cells, while ensuring ongoing tissue repair and maintenance through periodic re-seeding of somatic stem-cell pools with autologous TMM-deficient cells whose telomeres have been lengthened ex vivo.
The fifth biannual Strategies for Engineered Negligible Senescence biomedical conference is just days away. Getting ready for the trip has cast my mind back not only to previous meetings of this exciting interdisciplinary series, and also to the recent 40th meeting of the American Aging Association (AGE).
As we have previously reviewed, a comprehensive suite of rejuvenation biotechnologies must include the removal of extracellular aggregates from aging cells and tissues.
As we've noted previously,
Efficient, safe methods of gene therapy will be essential enabling technologies for the repair or obviation of several of the cellular and molecular lesions driving age-related disease and dysfunction, notably the accumulations of mutations in mitochondrial and nuclear DNA (including the medium-term obviation of the latter through WILT), as well as the introductio
Age-related accumulation of mutations in mitochondrial DNA (mtDNA) is widely suspected to play an important role in the degenerative aging process, albeit that controversy remains as to the mechanism(s) linking the two. Large deletions in mtDNA seem an especially likely culprit ...
It has been an exciting period ever since Dr. Doris Taylor of the University of Minnesota's Center for Cardiovascular repair outlined her results prior to publication in 2008 at the Foundation's Understanding Aging: Biomedical and Bioengineering Apporoaches conference at UCLA.
Much of the distraction in the literature of biogerontology, and an even higher ratio of studies cited and promoted in the popular media and the dietary supplement industry, derives from methodologically-poor lifespan studies in mice (or occasionally rats).
I'm delighted to be able to share with you our research report, prepared for the first 10 months of 2010, by Tanya Jones (our Director of Research Operations), working with our researchers and my CSO Team. I thought it would be of interest to our supporters, and serve as a precursor to our 2010 Year End Report, which is currently under production as part of our finalizing our 2010 accounts.
The early free radical theory of aging was based on Dr. Denham Harman's remarkable insight that much of the cellular and molecular damage of aging bore strong resemblance to damage he observed in organisms exposed to ionizing radiation.(1) In subsequent decades, the theory -- and its later refinement into the mitochondrial free radical theory of aging(2,3) -- has gained wide acceptance, even as the challenges against it have mounted and risen in sophistication.
The often-mooted question of whether "aging itself" is or is not a "disease" has long been mooted in biogerontological circles, with a long-held rhetorical preference for asserting that it is not, but rather, that it is a risk factor for the specific diseases of aging.(1) By contrast, the same fundamental semantic dispute was initially resolved in the opposite direction with regard to age-related cognitive decline and dementia, beginning in the early decades after Alois Alzheimer and Emil Kraepelin first identified the pathological basis of the Alzheimer's disease (AD) until the ea
The degenerative aging of the immune system is responsible for an enormous burden of disease and disability, from the pain of recurrent Herpes zoster and postherpetic neuralgia, to elevated rates of chronic urinary tract infections, to complications in wounds, pressure sores, ulcers, and surgical incisions.
As we reviewed in a previous posting on a recent advance in genetic engineering with zinc finger nucleases (ZFNs),
Toward Full Pluripotency of Reprogrammed Cells -- And Cautionary Tale About Abandoning the 'Gold Standard'Posted by Michael Rae on December 09, 2010 | Chief Science Officer's Team
The intrinsic biological aging process is driven by the accumulation of damage to the cellular and molecular structures in tissues and organs, resulting from the biochemical side-effects of essential metabolic processes. In turn, this rising decay of cellular and molecular structures drives the age-related rise in disability, disease, dependence, dementia, and ultimate risk of death.
As noted in a previous post, the clearance of neurofibrillary tangles (NFT) and other intracellular aggregates is a key rejuvenation biotechnology to restore youthful function to aging brains, especially those with Alzheimer's disease (AD) and a range of other age-related neurodegenerative disorders.
SENS Foundation's CSO, Dr Aubrey de Grey, was first featured in Wired magazine in 2008, shortly before the Methuselah Foundation's initial USA-based conferences. Two years on, he's now returned in a more candid and detailed interview, discussing how the tactics involved in bringing rejuvenation biotechnologies to the attention of mainstream science have evolved and begun to bear fruit.
In September 2007 SENS Foundation's Chief Science Officer, Dr Aubrey de Grey, together with co-author Michael Rae published Ending Aging - an accessible description of the SENS platform. The book speaks to a broad audience, without "dumbing down" the science in any way, and is thus the ideal resource for both biologists and non-biologists who want to learn more about SENS and its implications.
Neurofibrillary tangles (NFT -- cytoplasmic inclusions composed of phosphorylated and abnormally-cleaved species of tau protein) accumulate in the aging brain, and at higher levels in Alzheimer's disease and in vulnerable regions in a range of other neurodegenerative diseases; they are closely associated with neuronal death and with onset of clinical dementing disease.
A comprehensive suite of rejuvenation biotechnologies must include therapies that remove extracellular aggregates from aging cells and tissues.
In addition to its widely-anticipated potential to provide highly-effective therapies for genetic disorders, somatic gene therapy is an essential enabling technology for the repair or obviation of several of the cellular and molecular lesions driving age-related disease and dysfunction (notably the accumulations of mutations in mitochondrial and nuclear DNA).
A comprehensive suite of rejuvenation biotechnologies must include the removal of extracellular aggregates from aging cells and tissues. The most clinically-advanced such biotechnology is immunotherapy against aggregated beta-amyloid protein (Aβ), a characteristic neuropathological lesion that accumulates in the brain in Alzheimer's disease (AD) patients and as part of "normal" brain aging.(1)
Age-related accumulation of mutations in mitochondrial DNA (mtDNA) are widely suspected to play an important role in the degenerative aging process, albeit that controversy remains as to the mechanism(s) linking the two.
Haematopoietic stem cells (HSC) and their progeny from exhibit a range of functional declines during biological aging. Most research probing the reasons for these declines have focused on aging damage accumulating in the HSCs themselves, such as the rising burden of oxidative stress and DNA damage (and, as a result, senescent cells) in the compartment.
Last summer, California-based LifeStar Institute assembled a panel of leaders in the science of aging to ask them the question at the core of their research. How far can the potential of new biomedical therapies to slow, arrest, or even reverse the damage of aging be brought to bear against the challenge of global graying?
Tissue engineering and cell therapy are an essential plank in the Strategies for Engineered Negligible Senescence (SENS) platform of regenerative engineering. These biotechnologies are most obviously central for direct clinical use in repairing and replacing cells and tissues "injured by trauma, damaged by disease or worn by time" (as William Haseltine first defined regenerative medicine (1)).
A variety of extracellular aggregates accumulate in the aging body, and strong evidence exists for their contribution to age-related morbidity and pathology. This makes them targets for regenerative engineering: the rescue of youthful tissue function through the restoration of structure from such damage. In the case of extracellular aggregates, the most promising biomedical approach is their clearance with targeted immunotherapy.
As anyone following the field will know, the derivation of induced pluripotent (iPS) cells reprogrammed from differentiated somatic cells offers a remarkable promise: the ability to generate donor-specific pluripotent stem cells, without the "ethical" confusion that has so unfortunately retarded the progress of somatic cell nuclear transfer (SCNT) research.
In late 2008, we reviewed then-unpublished work by Dr. Mark Pepys, who was working on an ambitious project anticipated to allow for the disaggregation of nearly all disease-associated amyloids. Dr. Pepys subsequently accepted an invitation to present those early results at the fourth SENS scientific conference(1).
In a previous update, we reviewed a recent report from a group looking to select the most active beta-amyloid (Abeta)-targeting antibodies from pooled human immunoglobulin for injection (IVIgG). As we noted there,several small, early-phase clinical trials of IVIgG for Alzheimer's disease have reported promising results. Moreover, the IVIgG preparations used in these trials are already available and approved for other indications.
Aggregates of beta-amyloid (Aß) and other malformed proteins accumulate in brain aging and neurodegenerative disease, leading progressively to neuronal dysfunction and/or loss. The regenerative engineering solution to these insults is therapeutic clearance of aggregates, extracellular (such as Aß plaques) and intracellular (such as soluble, oligomeric Aß).
To date, all successful interventions into the biological aging process in experimental animals have entailed modulation of basic metabolic pathways, generally through genetic or dietary manipulation.(0) Of these, the earliest, most well-studied, and arguably the most robust, is Calorie restriction (CR): the reduction in dietary energy intake, without compromise of essential nutrients.(1,2) With few exceptions, CR retards the biological rate of aging in nearly every species and strain of organisms in which it has been tested, ranging from rotifers, through small multicellular invertebrates,
Progress toward the goal of tissue rejuvenation via stem cells and tissue engineering ("RepleniSENS") is badly hampered by the surprising fragility of human embryonic stem cells (hESC) relative to mouse ESC (mESC). Unlike their murine counterparts, hESC undergo extensive cell death following enzymatic single-cell dissociation; as a result, researchers are forced to rely on laborious mechanical microdissection, or on narrowly-control enzymatic dissociation that ensures that hESC remain above a minimum cluster size.
Abeta Epitope DNA and Peptide Vaccination: Bridging the 'Therapeutic Threshold' for Cognitive Aging and Alzheimer's DiseasePosted by Michael Rae on April 26, 2010 | Chief Science Officer's Team
Recent years have seen both substantial progress, and significant frustration, in the preferred regenerative engineering approach to the treatment and prevention of Alzheimer's disease (AD), and the eventual regeneration of genuinely youthful cognitive function: immunotherapeutic clearance of beta-amyloid (AmyloSENS).
At the core of SENS Foundation's strategy to comprehensively cure the diseases and disabilities of aging is a new biomedical heuristic: regenerative engineering.(1-3) To date, the dominant therapeutic strategy for both specific age-related diseases and (to the extent that it has been contemplated) the degenerative biological aging process itself, has been based on altering metabolic pathways.
To develop an unbreachable defense against cancer, SENS Foundation is pursuing the WILT (Wholebody Interdiction of Lengthening of Telomeres) strategy (OncoSENS) of systematically deleting genes essential to the cellular telomere-maintenance mechanisms (TMM) from all somatic cells, while ensuring ongoing tissue repair and maintenance through periodic re-seeding of somatic stem-cell pools with autologous TMM-deficient cells whose telomeres have been lengthened ex vivo.
To date, three of the thirteen OXPHOS genes still encoded in the mitochondria have been allotopically expressed (AE) in human cells with mutated versions of the same gene, and thereby rescued a respiratory defect: ATPase61,2, ND43, and ND14.
Elan/Wyeth's bapineuzumab has advanced further down the clinical pipeline than any other immunotherapy targeting removal of Abeta from the AD brain. While its lead status has brought much attention to this damage-repair approach, its prominence has at the same time had the unfortunate side-effect of eclipsing numerous alternative Abeta immunotherapies that span the range of earlier stages of development.