Michael Rae discusses the role of senescent cells in the brain during aging, and how eliminating those cells could prevent diseases like Alzheimer's and Parkinson's.
Article by Michael Rae about recent and forthcoming regulatory reforms required to support the testing of new therapies for Alzheimer's and other age-related diseases.
Question Of The Month #16: Any Rejuvenation Relevance for Roundworm Reproduction? Part of Michael Rae's regular column from the Foundation's newsletter.
Alpha-synuclein aggregates are a key form of aging damage in the brain, linked to a spectrum of symptoms in Parkinson's disease beyond the classic motor symptoms. The first amyloSENS-style immunotherapy to clear this pathology out of the brain was advanced into clinical trials by Austrian biotech firm AFFiRiS AG. Now two more such therapies have entered human testing. Although the trials are in their earliest stages, they bring the hope that this rejuvenation biotechnology will begin preventing and reversing Parkinson's disease and less specific disorders of aging soon.
Question of the Month #15: Would Other Rejuvenation Biotechnologies Keep Us Cancer-Free? Part of Michael Rae's regular column from the Foundation's newsletter.
Question of the Month #13: How Can Thymic Regeneration Combat Age-Related Autoimmunity? Part of Michael Rae's regular column from the Foundation's newsletter.
Question of the Month #12: Energy-Carrying Molecules to Boost Aging Mitochondria? Part of Michael Rae's regular column from the Foundation's newsletter.
Question of the Month #11: Are Mitochondrial Mutations Really All That Important? Part of Michael Rae's regular column from the Foundation's newsletter.
Question of the Month #10: Rejuvenation for calcification amelioration? Part of Michael Rae's regular column from the Foundation's newsletter.
Question of the Month #9: What is the role of novel diagnostics in rejuvenation biotechnologies? Part of Michael Rae's regular column from the Foundation's newsletter.
Question of the Month #8: Aging Damage and Early Early Detection. Part of Michael Rae's regular column from the Foundation's newsletter. Q: "Because the cellular and molecular damage of aging is a by-product of metabolism, I have always assumed that it accumulates throughout our entire lives – from when we are a baby until we die. Is this true? Is there any research showing that very young children have low levels of tissue-stiffening crosslinks, extracellular aggregates like beta-amyloid, or intracellular aggregates (like lipofuscin or the ones driving atherosclerosis) in their tissues?"
α-synuclein (AS) neuropathology is one of the key forms of aging damage driving Parkinson's disease (PD) and aspects of the "normal" loss of cognitive and autonomic nervous control with age. Immunotherapy targeting the clearance of AS aggregates from aging neurons is a key rejuvenation biotechnology for the prevention and reversal of brain aging and PD. The first human clinical trial of an AS-clearing active vaccine in early-stage PD patients was initiated in the summer of 2013. The highly promising results of this first trial have now been announced, and have led to a followup study and the launch of an EU consortium to test it for additional AS-related indications. Contemporaneously, two human trials have been initiated using a second AS-clearing rejuvenation immunotherapy, this one using infused monoclonal antibodies as a passive immunotherapic rather than an antigen-based vaccine. We review progress in this area and its links to the wider progress in PD-related rejuvenation biotechnology.
A recent interview with SENS Research Foundation Chief Science Officer Dr. Aubrey De Grey evoked an eruption of worldwide media coverage, because of a brief comment he made to the effect that rejuvenation biotechnology could eliminate menopause within twenty years. This post gives some examples of foreseeable biotechnologies carrying us toward that eventuality.
Rejuvenation of the aging brain will require the integrated application of several core rejuvenation biotechnologies, including notably those that remove intra- and extraneuronal aggregates implicated in neurodegenerative aging and mature cell therapy. Numerous aggregate-clearing rejuvenation biotechnologies are now in human trials, whereas mature cell therapy for the brain is a more challenging goal and will not be available for some time. In this context, an alternative approach to maintaining the viability of aging neurons could complement aggregate-clearing therapies to preserve neurons until neural replacement and reinforcement matures. In this post we explore the potential of one recently-emerged approach: inhibition of the unfolded protein response (UPR).
Aggregates of the neuronal membrane protein α-synuclein accumulate in the aging brain and are implicated in the non-motor symptoms of Parkinson's disease and related disorders, as well as subtler age-related dysfunction of the autonomic and peripheral nervous system. Preclinical evidence demonstrates that immunotherapeutic clearance of these aggregates in transgenic animals rescues Parkinson's-like behavioral and cognitive dysfunction. With support from a major Parkinson's research and advocacy charity, an Austrian biotech firm has advanced a first-in-class rejuvenation biotechnology targeting α-synuclein aggregates into Phase I clinical trials.
The need for disease-modifying therapies in Alzheimer's disease, and the strength of the case for aggregated beta-amyloid as a target, have recently driven substantial regulatory reform and innovations in clinical trial design to open up the path for faster and more effective human testing and approval of novel Alzheimer's therapeutics. The first fruits of these changes are a series of large, late-stage clinical trials of immunotherapies targeting the removal of beta-amyloid from the brain. These reforms and precedents open up the path for human testing and approval of future rejuvenation biotechnologies.
Engineering of new thymus tissue is a key rejuvenation biotechnology, to prevent or reverse the dramatic rise in morbidity and mortality from infectious disease that begins in the seventh decade of life. SENS Research Foundation is supporting thymus engineering research at the Wake Forest Institute of Regenerative medicine. In an important first, researchers at UCSF have derived a simple thymus-like tissue transplant that gave promising signs of restoring the ability to help form mature T-cells.
Two quarter-century long studies on the effects of Calorie restriction in nonhuman primates have come to opposing results. What do these results mean for the human translatability of CR, and the future of therapies to prevent and cure the diseases and disabilities of aging?
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
"Reprogramming" of adult differentiated cells into pluripotent stem cells is an exciting method in biology that holds enormous promise for rejuvenation biotechnology. Now, for the first time, Dr. Su-Chun Zhang and coworkers at the University of Wisconsin-Madison have successfully generated neurons from reprogrammed nonhuman primate cells, transplanted them back into the same animal's brain, and seen them successfully and cleanly integrate into the local tissue.
SENS Research Foundation has established a new research center at Cambridge University and a collaboration with scientists at Yale University. The mission: develop new therapies to repair a critical form of molecular damage that drives the slow stiffening of the arteries with age. Such rejuvenation biotechnologies could prevent such deadly and disabling diseases of aging as stroke and kidney disease.
The preliminary results of a clinical trial for a disease of "premature aging" - Hutchinson-Gilford Progeria Syndrome (HGPS) - are hopeful and inspiring. However, they cannot directly inform the development of rejuvenation biotechnologies; although the symptoms of HGPS are similar to those observed in aging, there is no evidence to suggest that the underlying mechanism is pathologically significant in those not afflicted with the disease.
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, particularly examining how telomerase activity relates to the development of cancer.
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.
The promising results of immunotherapy for the treatment and prevention of Alzheimer's disease has sparked an interest in utilizing the same approach for other forms of aging damage, including the clearance of pathological tau species from within neurons. A group led by Dr. Lars Ittner of the University of Sydney has recently published promising results from studies using a vaccine targeted at the neurofibrillary tangles (NFTs) that are characteristic of established tau accumulation.
APBs - protein complexes associated with telomeric DNA in ALT (Alternative Lengthening of Telomeres) cancer cells - are the leading candidates for the sub-cellular site at which the ALT mechanism occurs. Recent work involving the generation of artificial APBs has shed light on their composition and function, providing hints as to how ALT might be disabled.
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
Parkinson's disease is characterised by the loss of dopaminergic neurons from the substantia nigra, and cell therapy is being actively pursued as a means to replace the losses. Most trials to date have used fetal tissue, an approach that although transiently effective is unscalable and prone to immune rejection. Human dopaminergic neurons differentiated from stem cells have historically had poor therapeutic efficiency, but a new study using an improved differentiation protocol has shown much more positive results.
"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.
Aggregates of beta-amyloid protein (Abeta) and other malformed proteins accumulate in both "normal" brain aging and neurodegenerative disease, leading to neuronal loss. Their removal by immunotherapy is a central plank of the SENS platform, and the most clinically advanced. Gantenerumab, a new fully human anti-Abeta monoclonal antibody, has just completed a Phase I trial.
The elimination from the body of telomerase, the enzyme used by most cancer cells to maintain their DNA through unlimited numbers of cell divisions, is the central component of the WILT (Whole-body Interdiction of Lengthening of Telomeres) strategy proposed by SENS Research Foundation as a universal and unbreachable defence against all forms of cancer. Concerns have been raised, however, that telomerase may have other biologically important functions, making its elimination dangerous or impossible. Fortunately, recent work by Nobel laureate Carol Greider indicates a lack of any such activity.
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). AGE was the first, and remains the premier, professional scientific organization focused specifically on biomedical research in aging.
A comprehensive suite of rejuvenation biotechnologies must include the removal of extracellular aggregates from aging cells and tissues, particularly the brain. Recent work indicates that up-regulation of the activity of the native lysosomal pathway for clearance of beta-amyloid (Abeta) by the small molecule PADK can reverse existing Alzheimer-like pathology in mouse models, although caution is required in interpreting these results in the context of human disease.
Neurofibrillary tangles - accumulations of abnormal tau protein - are thought to play a central role in Alzheimer's disease and other neurodegenerative conditions. Here we review a recent report in which immunotherapy was used to clear tau aggregates from a highly accurate mouse tauopathy model, resulting in functional recovery on multiple cognitive tests.
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. A recent paper from the Scripps Institute demonstrates a major step in this direction with the successful use of helper-dependent adenoviral vectors to rescue cells defective in lamin A, without detectable mutational side-effects.
At the third SENS conference, Dr. Samit Adhya of the Indian Institute of Chemical Biology presented a proof-of-principle for the use of an RNA import complex adapted from the parasite Leishmania to import arbitrary antisense RNA strands into mammalian mitochondria, reducing levels of a target protein by RNA interference. In a new study, Adhya's group reports the successful use of the same technique to deliver mRNA sequences corresponding to proteins of the electron transfer chain, rescuing mitochondrial function in cells with mutations or deletions in those genes.
Dr. Doris Taylor, the researcher whose team successfully engineered a live, beating rat heart via the technique of decellularisation and reseeding, has announced progress towards repeating the process with human tissue. Press reports based on Dr. Taylor's presentation at the American College of Cardiology's 60th Annual Scientific Session indicate that the hearts are growing well and are expected to begin beating within the next few weeks.
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). In these studies, an increase in mean or maximal lifespan is reported, relative to short-lived controls, and claimed to be informative about the universal, degenerative aging process and the prospects for extending healthy life in humans living in the developed world.
The free radical theory of aging suggests that reactive oxygen species (ROS) and similar chemicals are responsible for a large part, or perhaps all, of the molecular and cellular damage that accumulates in aging bodies. However, more detailed analysis has revealed that some free radicals have essential signalling functions within the cell. These functions are likely to explain some of the failure of antioxidant therapy to extend lifespans in model organisms.
Two recent publications clearly refute the principle arguments in favour of a distinction between "normal" cognitive aging, and pathological conditions such as Alzheimer's disease. Instead, it is increasingly apparent that the "normal" cognitive decline observed in all elderly and some middle-aged individuals is simply an earlier stage of the frank neuropathology observed in neurodegenerative disease. We emphasise that treating such conditions at this earlier, pre-clinical stage is likely to be more effective, as well as being more humane.
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. Most prominently, it underlies the meteoric rise in mortality from respiratory infections with age: influenza, pneumonia, and septicemia rise from being negligible causes of death in healthy middle-aged adults in the USA, to emerge amongst the top 10 causes of death in adults over the age of 55, with mortality rates climbing with each successive year of aging.
Zinc finger nucleases (ZFNs) are engineered DNA-binding proteins with remarkable, highly programmable sequence-specificity. However, their widespread use has been slowed by licensing issues and the technical difficulty of synthesising new variants. A new platform, CoDA (context-dependent assembly), promises to make these exceptionally useful tools available to a far greater number of researchers.
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
Induced pluripotent stem cells (iPSCs) are among the most exciting recent developments in biomedicine, overcoming immunological and ethical issues associated with the use of embryonic stem cells (ESCs). However, reasonable doubt remains regarding whether iPSCs do in fact have the full biological and therapeutic potential of ESCs. Work at the Harvard Stem Cell Institute recently produced the first "all-iPSC" live mice, a milestone on the road to establishing full equivalence between the two methods.
Resveratrol, a polyphenol famously found in wine, has previously been shown to extend lifespan in some naturally unhealthy rodent strains - but unfortunately does not show the same benefits in healthy, naturally long-lived mice. Meanwhile rapamycin, an immunosuppressant drug, has now become the first substance confirmed to at least moderately extend maximum lifespan in healthy mice.
The clearance of beta-amyloid (Abeta) and other protein aggregates by immunotherapy is a key rejuvenation biotechnology to restore youthful function to aging brains, especially those with Alzheimer's disease (AD) and other neurodegenerative disorders. Initial trials using anti-Abeta vaccines have demonstrated concomitant reductions in early-stage tau aggregates, but not in mature neurofibrillary tangles, suggesting that such vaccines would be optimally deployed much earlier in the disease process - or in combination with anti-tau vaccines.
Neurofibrillary tangles (NFTs - cytoplasmic inclusions composed of abnormal species of tau protein) accumulate in the aging brain, particularly in neurodegenerative disease, where they are closely associated with areas of neuronal death. The urgency of tackling tau accumulation in particular has become more apparent after recent studies revealed that clearance of beta-amyloid alone achieves only moderate clinical benefits, with continued pathology attributed in particular to persistent NFTs.
The well-known beta-amyloid protein that plays a major role in Alzheimer's disease is only one of those which accumulate in aging bodies. Cardiac amyloidoses, caused by aggregation of the proteins transthyretin and atrial natriuretic peptide, are already the dominant cause of death in supercentenarians (those 110 years of age or older) and are expected to become much more widespread in an increasingly aged general population and as improved treatment options become available for other age-related diseases. SENS Research Foundation has recently launched a project exploring the use of catalytic antibodies - which actively degrade their target, rather than merely binding to it - to remove such aggregates.
A technique combining the sequence-specific DNA-cleaving property of zinc finger nucleases (ZFNs) and the localisation function of transcription activator-like effectors (TALEs), creating a new class of composite proteins called TALE nucleases (TALENs), shows considerable promise for expanding the range of genomic sites susceptible to precision engineering.
Comprehensive rejuvenation must include the removal of extracellular protein aggregates from aging tissues. Immunotherapy - in which the immune system is encouraged to recognise and clear a particular protein - is the most clinically-advanced biotechnology for this purpose, but has some limitations. Notably, rapid immune clearance of a large volume of protein can cause severe inflammatory side-effects; also, efficacy depends on the patient's response to vaccination, which declines dramatically in the elderly patients most in need of therapy. A new approach using catalytic antibodies that directly degrade the amyloid proteins may overcome these problems.
Mutations to the mitochondrial DNA (mtDNA) are thought to be a major source of aging-related increases in oxidative stress. The candidate SENS therapy, allotopic expression, involves the production of mitochondrial proteins from the nuclear DNA and their import into the organelle. An alternative mechanism where RNA, rather than protein, is imported is now providing another avenue for research.
Haematopoietic stem cells (HSC) exhibit a range of functional declines during biological aging. There has been comparatively little exploration of the possibility of outside causes for age-related HSC dysfunctions, such as the role of age-related shifts in the systemic and local environment and the aging of the bone marrow niche. In a recent report, Dr. Amy Wagers' group have demonstrated the reality - and the reversibility - of both of these influences on age-related HSC dysfunction.
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?" The most important conclusion reached by the participants was that an aggressive program of investment to realize that potential is not only justified, but necessary on humanitarian, economic and social grounds.
A recent landmark report from researchers at Yale and Duke universities heralds a significant advance towards the tissue engineering of replacement lungs. Decellularised donor lungs repopulated with progenitor cells were matured in vitro and then implanted into living rats, where the tissue participated in gas exchange to an extent functionally approaching that of native lung tissue. This study represents a crucial proof-of-principle that the decellularisation/repopulation approach can be effective in another complex organ.
Neurites - projections from a neuron's cell body - become structurally abnormal in proximity to the extracellular aggregates that occur in both neurodegenerative disease and "normal" cognitive aging. These structural abnormalities have been suggested to play a role in cognitive pathology, by disrupting normal synaptic integration. Active immunotherapy against beta-amyloid (using the AN1792 antibody) has now been shown to reverse much of this structural deformity, even in cases where plaque clearance is incomplete.
New insights into the role of AID, a DNA demethylase, in the reprogramming process that produces induced pluripotent stem (iPS) cells are expected to allow greater efficiencies and permit the elimination of clinically problematic viral vectors and proto-oncogenes.
Serum amyloid P component (SAP) is a universal constituent of amyloid deposits, apparently regardless of the disease in question (and thus the other proteins present). Although methods have been developed to eliminate SAP from the body, this approach could have potentially serious side-effects. We announce a new SENS Research Foundation-funded project to tackle amyloid accumulation via the alternative, more direct approach of catalysing degradation of the pathogenic protein components.
The discovery of natural antibodies against beta-amyloid, the major component of the plaques that characterise Alzheimer's disease, is a promising suggestion as to the potential effectiveness of a relatively straightforward immunotherapy.
Affibodies are artificial, antibody-like proteins generated through protein engineering techniques. ZAβ3, an affibody that targets amyloid-beta (Abeta), has been shown to prevent plaque formation and neurotoxicity in animal models of Alzheimer's disease. Affibodies like ZAβ3 might have important practical advantages over antibody-based Abeta-clearing agents, making this a promising new approach.
Widespread optimism about the life-extension potential of calorie restriction (CR) is tempered by doubt that any significant number of people will ever adopt it as a lifestyle. However, thus far the search for "CR mimetics" – drugs that convey the same benefits on a normal calorie intake - has been fruitless. Here we review some of the prominent examples.
Unlike mouse embryonic stem cells (ESCs), human ESCs are highly prone to death after enzymatic dissociation from a growing cell cluster; as a result, researchers are forced to rely on far more laborious methods for their expansion. New research at the Scripps Institute has revealed the molecular basis for this frustrating limitation, and also uncovered two small-molecule drugs able to greatly improve the cells' survival.
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
Immunotherapeutic clearance of beta-amyloid is the preferred regenerative medicine approach to the treatment and prevention of Alzheimer's disease (AD), but existing attempts to develop such therapies have been fraught with side-effects and limited efficacy, as well as concerns about clinical translatability. A new approach using DNA vaccines is showing great promise, and has the potential to be safe and cheap enough for deployment in pre-clinical AD - before any irreversible memory loss can occur.
Biomedical research has traditionally focused on identifying and correcting the abnormalities in metabolic pathways that lead to disease states. However, this approach suffers numerous side-effects due to the complexity of metabolism. It is also inappropriate to treating many age-related diseases, which arise as a result of damage accumulated over decades of normal function. Regenerative engineering, by focusing instead on the removal of this damage, largely avoids both of these chronic problems.
In addition to telomerase, some cancer cells become immortalised via the phenomenon known as ALT ("Alternative Lengthening of Telomeres"). A new paper published in Nature suggests that Zscan4, a gene essential for telomere maintenance in embryonic stem cells, may be the driver of the ALT mechanism.
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, thereby rescuing a respiratory defect. Now we have the first report of a new gene, COX2, being allotopically expressed in yeast, by mutating the gene to overcome the hydrophobicity of the mitochondrial membrane; a similar mutation has been shown to underlie the ability of the unusual case of the soybean COX2, which is a case of a native nuclear-encoded COX2 gene.
Intravenously delivered immunoglobulin G (IVIgG) is a mixture of antibodies extracted from human blood which has demonstrated promising preliminary results in clearing the beta-amyloid (Abeta) deposits that drive the pathogenesis of Alzheimer's disease. A recent study compares multiple commercial sources of IVIgG and finds significant differences in their Abeta-binding activity, suggesting that results from impending clinical trials are likely to be highly dependent on the specific "brand" of IVIgG in use.