Reading Level: In-Depth

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.

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.

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.