Longevity Medicine – State of the Art 2024

In 2005, the former artificial intelligence researcher who became a biologist, Aubrey de Grey, proposed a detailed plan called “strategies for engineered negligible senescence” (SENS), aimed at preventing age-related physical and cognitive decline. Two years later, he published the book “Ending Aging: The Rejuvenation Breakthroughs that Could Reverse Human Aging in Our Lifetime”, in which he wrote in detail about seven issues and measures how to repair them (table taken from Wikipedia):

Issue	Proposed countermeasures
Extracellular aggregates	Immunotherapeutic clearance
Accumulation of senescent cells	Senescence marker-targeted toxins, immunotherapy
Extracellular matrix stiffening	AGE-breaking molecules, tissue engineering
Intracellular aggregates	Novel lysosomal hydrolases
Mitochondrial mutations	Allotopic expression of 13 proteins
Cancerous cells	Removal of telomere-lengthening machinery
Cell loss, tissue atrophy	Stem cells and tissue engineering

Since almost 20 years have passed since then, I contacted the SENS Foundation to get an update about these strategies and especially to learn which have been implemented in clinical practice so far. I received a friendly response from Michael Rae, the co-author of de Grey’s book. He wrote:

“Certainly none of the rejuvenation biotechnologies we outlined in the book have become common clinical practice yet: while Dr. de Grey and SENS Research Foundation are working hard to accelerate the development of rejuvenation biotechnologies to remove, repair, replace, or render harmless the cellular and molecular damage that accumulates with biological aging in our tissues, most rejuvenation biotechnologies are still quite some time away from clinical trials, let alone routine clinical practice — and certainly all the ones that we are actively researching are. Indeed, developing longevity therapies described in the book is the whole reason SRF exists!

The one rejuvenation biotechnology that has successfully passed through Phase III clinical trials and is an FDA-approved therapy is antibody-based removal of the sticky beta-amyloid protein that plagues the brains of people with Alzheimer's disease. The two that have been approved are aducanumab/Aduhelm and Leqembi (lecanemab) (the manufacturer is in the process of winding down the former in favor of the latter), and a third (donanemab) is expected to be approved soon.”

More about these breakthrough therapies can be found at these webpages:

https://www.sens.org/from-parachutes-to-jetpacks-clearing-brain-beta-amyloid-with-donanemab-or-lecanemab-works/

https://www.sens.org/amylosens-alzheimers-marathon-decathlon/

He further wrote: “There are numerous such immunotherapies currently undergoing late-stage trials in Alzheimer's patients and also people with dominantly-inherited familial Alzheimer's mutations who have not yet exhibited symptoms — and you may be aware of the important recent approval (in the US) of aducanumab/Aduhelm, which although not unproblematic could still prove itself effective if given long enough and early enough in the neurodegenerative aging process. And it in turn is likely to open the door to many other promising immunotherapies.

The Aduhelm precedent is likely to set a valuable precedent for still other rejuvenation biotechnologies. The most obvious cases are trials of similar immunotherapies targeting alpha-synuclein in people with early-stage Parkinson's disease and aberrant tau in Alzheimer's and other neurodegenerative aging diseases.

Additional cases are legitimate clinical trials of stem cell therapies for Parkinson's disease, several kinds of blindness, and a few other indications (these are entirely different from the unethical stem cell treatments that are being offered for money by physicians and private clinics); and trials of allotopic expression of mitochondrially-encoded proteins from the nucleus, which have been tested in patients with inborn rather than age-acquired mutations in particular mitochondrial genes.”

Additionally, some drugs to destroy senescent cells are entering clinical trials. There is some information on them on the SENS website:

https://www.sens.org/research/introduction-to-sens-research/deathresistant-cells
https://www.sens.org/enhancing-innate-immune-surveillance-of-senescent-cells/
https://www.sens.org/identification-and-targeting-of-noncanonical-death-resistant-cells

I am grateful to Michael Rae that he took the time to write this long reply. In my humble opinion, it is a pity that not more of de Grey’s ideas have been implemented in the past 20 years, but apparently medical science is developing at a rather small pace compared to computer science.

Claus D. Volko