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    SENS4 (Strategies for Engineered Negligible Senescence)

    Melanie Swan, MS Futures Group, m@melanieswan.com, +1-415-505-4426

    September 13, 2009; http://melanieswan.com/documents/SENS4_summary.pdf

Introduction

    The fourth annual SENS (Strategies for Engineered Negligible Senescence) Foundation’s rdthconference was held at Queens’ College in Cambridge, UK, September 3 7, 2009

    (program). SENS conferences are distinguished from other biogerontological and aging

    research conferences by having more of an applied focus on anti-aging therapies. The

    main sub-fields of aging research covered at SENS4 were intracellular and extracellular

    junk build-ups, telomeres and cancer, immunology, therapeutic delivery, stem cells and

    tissue engineering.

Broad conference themes

    Three and half days of conference talks were combined with late-night poster sessions

    and numerous coffee breaks, meals and punting on the River Cam to provide ample

    opportunity for the 200 or so attendees to discuss new ideas in anti-aging research. Some

    overall themes of the meeting were:

    ? Systems level thinking, a deeper conceptualization of aging as a variety of

    interconnected phenomena and the trade-offs in turning different elements on and

    off, how manipulating one dynamic impacts other related processes. Exemplar of

    this systems level approach was a study uniting genetics, virology and proteomics

    to find that the presence of HSV1 (Herpes simplex virus 1) in the brains of ApoE4

    carriers confers a strong risk of Alzheimer’s Disease (60%), which perhaps can be

    remedied by a protein vaccination to reduce HSV1 latency in the brain (abstract).

    ? Humans are complex, life extension strategies that work in lower organisms (e.g.;

    yeast, plants, worms, flies), such as any one of 200 knock-out genes in mice or

    CR (caloric restriction), may not work or definitely will not work in the more

    complex regulatory systems of higher mammals such as humans.

    ? Holding multiple possibilities in mind simultaneously as the detailed truth is

    probed. The notion of complex processes continues, for example, the idea that

    inflammation and plaques are to be eliminated vs. the idea that they are the body’s

    protective response to the real underlying disease trigger.

    ? Waste-clearing a lot of conference content was related to different strategies

    for removing the intracellular and extracellular junk that builds up in aging. Ideas

    featured the use of one cell or molecule to bind to and clear waste molecules,

    enzyme replacement therapies and anti-inflammation therapies.

    ? Aging relates to physical state and cognitive function, both areas must be

    improved to combat aging. Improvements are sought for detecting cognitive

    impairment, for example in vivo biomarker diagnostics for Alzheimer’s Disease

    that identify plaques and Abeta aggregates (abstract). http://melanieswan.com/documents/SENS4_summary.pdf Page 1

? Use of genomics there is starting to be a linkage between genomics and aging

    pathologies, particularly a hybrid approach of genomics plus biomarkers to

    diagnose and direct courses of treatment. An early look at this was provided in a

    talk entitled Genetic Variation and the Pathways to Successful Ageing.

    Highlight talks (in order of appearance)

    As usual, SENS Foundation Chief Science Officer Aubrey de Grey’s conference program

    curation was excellent and there were many interesting lectures by speakers from around

    the world. While it is hard to single out any talks, a few examples stand out as being

    exceptional in extending the conceptual boundaries and solutions in remedying aging:

    ? Mitochondria-targeted plastoquinone derivatives as anti-senescence drugs,

    Vladimir Skulachev, Moscow State University, Moscow, Russia

    Using a hydrophobic cation, SkQ1 (a structural analog of plastoquinone), to

    increase lifespan by reducing mitochondrial reactive oxygen species (ROS). The

    SkQ1 molecule will be entering clinical trials in the fall of 2009 with a Russian

    pharmaceutical company for the treatment of glaucoma. (additional information)

? Treatment and prevention of amyloidosis, Mark Pepys, University College

    London, London, UK

    Taking advantage of the body’s natural mechanism of clearing away foreign

    plasma proteins by binding small molecules (e.g.; new molecule CPHPC) to

    uncleared waste (e.g.; harmful serum amyloid P (SAP)) to form a new protein for

    automatic disposal. The same method is being investigated to cross-link and expel

    other molecules such as transthyretin.

? Designing enzymes ab initio, Kendall Houk, UCLA, Los Angeles, USA

    Using computational physics and chemistry for de novo enzyme design; looking

    for theozymes, theoretical enzymes with the requisite binding sites and other

    properties via computational search and molecular dynamical simulation. A

    portfolio of new proteins and enzymes has been synthesized and tested, for

    example retro-aldolases and DielsAlderases, which may be able to remove the

    Advanced Glycation End products (AGEs) of aging.

? Femtosecond laser nanosurgery from shedding light on nerve regeneration to

    aiding in cancer diagnosis and therapy, Adela Ben-Yakar, University of Texas,

    Austin, USA

    Using in-vivo femtosecond laser nanoaxotomy on-a-chip with single-cell ablation

    capability for cancer treatment and other targeted therapeutics.

    ? Intranasal delivery of cells to the brain, Lusine Danielyan, University of Tübingen,

    Tübingen. Germany

    Using intranasal delivery of MSC (Mesenchymal stem cells) and glioma cells for

    the rapid (within 15 minutes) routing of neuro-therapeutics deep into the frontal

    cortex and striatum of mice. Additional investigation ensues regarding cell uptake

    percentage and cell survivability.

    http://melanieswan.com/documents/SENS4_summary.pdf Page 2

    ? Synthesis of programmable integrases, Carlos Barbas, Scripps, La Jolla, USA

    Providing a more specific alternative to the homologous recombination method of

    genome modification by using zinc finger proteins to reprogram serine

    recombinases. (automated web-based design tool for zinc finger proteins)

    ? Reprogramming Somatic Cells to Pluripotency Using Small Molecules, Justin

    Ichida, Harvard University, Cambridge, USA

    Using a functional reprogramming screen to identify small molecules that

    efficiently replace signaling factors taking fibroblasts back to iPS (induced

    pluripotent stem cells) for the purpose of safer stem cell derivation (iPS-derived

    cells tend to form tumors in mice).

Most contentious talks: oocyte rejuvenation and stem cell retrodifferentiation

    The two talks found most contentious by the attendees were Progress Towards Use of Adult Ovary-derived Stem Cells as Therapeutic Tools and Targets for Delaying Age-

    related Infertility and Menopause,” which discussed the possibility of using stem-cell based regenerative medicine to sustain ovarian function (fertility) in aging females and

    Retrodifferentiation and Aging: Harnessing Youth through Induction of Pluripotency in

    mature adult cells via Cell Surface Receptor Contact,” which discussed the

    retrodifferentiation of white blood cells using multiclonal antibodies into other cell types

    such as red blood cells, neurons and heart cells.

Multidisciplinarity: Zoomers and diamond mechanosynthesis

    As aging is an emerging and wide-ranging field, there are many interesting issues to

    cover regarding the social impact, policies, economics, culture, technical aspects,

    perception and public health system uptake of anti-aging therapies. Some of the talks in

    this vein included a look at an empowering rebranding of seniors as Zoomers, the demographic consequences of defeating aging, lifelogging and crack avoidance during cryopreservation using a magnetic field (the magnetocaloric effect) for uniform cooling.

    A multidisciplinary talk of particular note was the first public follow-up of University of Nottingham physicist Philip Moriarity’s work in determining whether simple diamond

    mechanosynthesis reactions are possible after receiving a $3m grant in August 2008. Unfortunately, there has not been any progress yet as Moriarity’s lab is awaiting the delivery of equipment to begin their work. Mechanosynthesis is relevant to aging in that

    Phase I of anti-aging includes the damage repair therapies outlined in a visionary way by

    the SENS program, but Phase II, to really attain indefinite human lifespan, may likely

    require the use of medical nanobots (as envisioned by Ralph Merkle, and Robert Freitas

    in the book Nanomedicine) of which mechanosynthesis (the formation of covalent

    chemical bonds using precisely applied mechanical forces to build diamondoid structures)

    is the foundational technology.

Immediately actionable research

    As with other aging conferences, it is always encouraging to find some research which

    can be implemented immediately. Three key ideas were mentioned at SENS4. First, from

    http://melanieswan.com/documents/SENS4_summary.pdf Page 3

a nutritional standpoint was a study regarding the consumption of blueberries, raspberries,

    strawberries (any berries, and really any fruit with skin; 4-8 oz per day), walnuts (1oz per

    day) and green tea (1 cup per day) to decrease the mental aspects of aging and maintain a

    healthy PUFA ratio (abstract).

A second practicable example was a study which found that French herbs, particularly

    savory, marjoram leaves, rosemary leaves, basil, sage and tarragon, when consumed as a

    tea or in capsule form (2 x 350mg savory capsule) provided an arNOX reduction from

    40% to 15% for 6-9 hours. ArNOX oxidizes (renders unhealthy) LDL (abstract).

Third, regarding exercise, was the suggestion of an IHT (intermittent hypoxic (low

    oxygen air) training) regimen of five minutes of exercise, five minutes of pausing

    intervals using a hypoxicator to simulate altitude training (abstract).

VC guide to anti-aging biotechnology investing

    Several promising startup companies focused on the nascent but obviously significant

    and growing anti-aging biotechnology space were present or discussed excitedly as they

    making progress in the implementation of anti-aging therapies:

    1. Epeius Biotechnologies, San Marino, CA, USA: Rexin-G, a tumor-targeted

    injectable gene delivery system

    2. FoldRx, Cambridge, MA, USA: small molecule therapeutics to treat protein

    misfolding diseases, and bind and clear undesired molecules

    3. Gencia Corporation, Charlottesville, VA, USA: mitochondrial DNA rejuvenation

    using the rhTFAM (recombinant-human mitochondrial transcription factor A)

    protein

    4. Genscient, Fountain Valley, CA, USA: novel chronic disease therapeutics by

    combining genomics and selective screening (a large Alzheimer’s Disease genetic

    study is in progress with Kronos and TGen)

    5. Knome, Cambridge, MA, USA: whole human genome sequencing (consumer

    offering)

    6. Neotropix, Malvern, PA, USA: oncolytic viruses for the treatment of solid tumors

    7. Pentraxin Therapeutics Ltd, London, UK: small molecule drug CPHPC

    specifically targeting SAP (serum form of amyloid P) and removing it from the

    blood and brains of patients with Alzheimer’s Disease

    8. Repeat Diagnostics, Vancouver, BC, Canada: telomere length measurement for

    total lymphocyte and granulocyte populations (consumer offering)

    9. Retrotope, Los Altos Hills, CA, USA: using isotope effect to slow down damage

    pathways and control metabolic processes associated with oxidative stress

    10. StemCor Systems, Inc., Menlo Park, CA, USA: bone marrow harvesting system

    11. T.A. Sciences, New York, NY, USA: telomerase activation via the single

    molecule TA-65, licensed from Geron Corporation (consumer offering)

    12. TriStem Corporation, London, UK: retrodifferentiation technology to create stem

    cells from mature adult cells

    http://melanieswan.com/documents/SENS4_summary.pdf Page 4

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