Reading Level: In-Depth

Summary: A new nanotechnology enables the selective targeting of senescent cells; in mice, it dramatically improves an age-related lung disease, and makes cancer chemotherapy safer and more effective. Now the scientists behind it have a startup and are headed toward human testing.

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.

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 #11: Are Mitochondrial Mutations Really All That Important? Part of Michael Rae’s regular column from the Foundation’s newsletter.

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.