Michael Rae

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.

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.