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.
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. We're delighted to now be able to make the afterword to the paperback edition, summarising progress since the initial hardback publication, available for free download.
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.
I am working on a new experiment with nonspecific peroxidase enzymes and ALE-modified proteins. I am reacting BSA with malondialdehyde (MDA) to modify it with fluorescent crosslinks, which I can measure using ELISA.
The 7KC-degrading bacterium I’ve been studying, Rhodococcus jostii RHA1, has two large gene clusters that are up-regulated by 7KC, but not cholesterol. In these two gene clusters lie a number of enzymes we believe are involved in 7KC degradation, including an enzyme that could reduce the 7-keto group to a hydroxyl. What makes this interesting to us is that while 7KC is highly cytotoxic, 7α-hydroxycholesterol (7αOH) is relatively harmless.
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.