June 1, 2020

Aging

#112 – Ned David, Ph.D.: How cellular senescence influences aging, and what we can do about it

"What you see in these diseases of aging is often the sort of unintended consequences of a system that was absolutely awesome for the young, at the expense of the old." — Ned David

Read Time 26 minutes

Ned David is the co-founder of Unity Biotechnology, a company developing senolytic medicines—molecules that target and destroy senescent cells in the human body. In this episode, Ned explains the science of cellular senescence and how it impacts the aging process. Ned discusses how senolytics may delay, prevent, treat, or even reverse age-related diseases, including cancer, cardiovascular disease, and neurodegenerative disease. As a serial entrepreneur, Ned also provides advice on how to transform a simple idea into the creation of a company.

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We discuss:

  • Defining longevity and the principles of aging [2:50];
  • The control knobs of aging and how we can turn them [15:10];
  • Role of cellular senescence in aging and cancer [27:00];
  • History of senescence in scientific study [40:30];
  • The cellular senescence paradox [46:00];
  • Developing medicines that target cellular senescence [52:15];
  • Ned’s lessons on risk analysis in business [1:05:15];
  • The search for a molecule that could eliminate senescent cells [1:15:15];
  • Senescent cell elimination example in osteoarthritic knees [1:30:30];
  • Extending lifespan by removing senescent cells [1:45:00];
  • Senolytic molecule example in macular degeneration reversal [1:52:30];
  • The future of senescent cell targeting [1:58:30];
  • The role of cellular senescence and metabolic syndrome [2:01:30];
  • The role of cellular senescence and brain health [2:03:30]
  • How building the company Kythera prepared Ned for his grander project of creating Unity Biotechnology [2:05:45];
  • Advice for someone considering an entrepreneurial career path versus an academic career path [2:08:50]; and
  • More.

§

Defining longevity and the principles of aging [2:50]

What does “longevity” mean to Ned?

“Well, longevity for me would be being able to live without the indignities that I’ve witnessed. We all witnessed in our lives all of these features of aging that seemed to be an escapable.”

“Longevity would be the ability to use what I know how to do just science, biology, and be able to change how we get to live our lives, to be free of these indignities.”

Principles of aging

Three principles:

  #1—Aging is not a rigid thing, it’s flexible and malleable 

  #2—Nature has “control knobs”

  #3—Natures control knobs can be “twisted” by humans (such as with drug development)

“So nature is clearly gone to town on this and created these marvelous examples of disparate lifespan, but sort of the same creature, the same biochemistry.”

First evidence that there were “control knobs”

  1—Very similar creatures have very different lifespans

  • Example: A hard clam (one that you could eat) lives about 40 years, but it has a deep ocean dwelling relative called the quahog clam that lives at least 500 years
  • Example in mammals: Tiny shrew (less than 1 year lifespan) vs. Bowhead whale (~200+ years)

  2—Cynthia Kenyon’s work in C. elegans (worms)

  • Kenyon showed that by knocking out a single gene (Daf-2) could double it’s lifespan
  • Later work suggested knocking out the daf-16 gene in combo with caloric restriction was perhaps the most extrapolatable insight to mammals

“To me, it was the Daf-2 to Daf-16 observation that opened up the field and said that there were these knobs that you could turn and you could get these radical impacts on longevity.”

 

The control knobs of aging and how we can turn them [15:10]

The control knobs of aging:

{end of show notes preview}

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Ned David, Ph.D.

Ned co-founded UNITY in 2011, largely because he thought it was “simply the coolest biology he had ever seen.” Before UNITY, Ned co-founded four other biotechnology companies that together raised over $1.5 billion in financing and today employ over 400 scientists, engineers, and business people. Ned builds companies because he sees company creation as a means to create technologies that change the world. Ned is a co-founder of Syrrx (acquired by Takeda), Achaogen (AKAO), Kythera Biopharmaceuticals (KYTH, acquired by Allergan), and Sapphire Energy. Ned holds pending and issued patents in fields such as nanovolume crystallography, antibiotic resistance, aesthetic medicine, and cellular senescence. He has served on the board of directors of Kythera Biopharmaceuticals, Sapphire Energy, and the Buck Institute for Research on Aging and is a member of the board of trustees of the University of California Foundation. Ned was named one of the Top 100 innovators in the world under 35 by the MIT Technology Review. He holds a Ph.D. from the University of California, Berkeley in Molecular and Cellular Biology and an A.B. in Biology from Harvard University. [unitybiotechnology.com]

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  1. Just saw the title of this one and couldn’t contain my excitement! Can’t wait to give it a listen.

  2. Very comprehensive, fun to listen to. Now how about any recent senolytics that I can actually buy and use? Any new science on quercetin and dasatanib? Is there anything better out there?

  3. Just an ingenuous question. One of the benefits of fasting is the increased level of apoptosis. Does it target senescent cells as well as errant ‘normal’ cells and is that why mice live longer on a restricted diet? As I said, an ingenuous question!

  4. Very interesting that you and your guest failed to make even a glancing reference to the part played by diet and nutrition in the development AND possible treatment of the maladies he is so eager to treat with drugs.

    • Yes I agree with you Lance.Though interesting I found the talk depressing because of the blinkered approach to the subject ‘Got a problem? Let’s find a drug’ seems to be the guest’s mantra.

  5. As noted by Lance and Mary, I too was disappointed that there was little to no discussion around how some of these same effects might be achieved with diet (i.e. IF) and nutrition. Of course, this discussion mostly centered around his scientific and entrepreneurial drive and focus on finding drugs to solve health issues, which, as a scientist, engineer and entrepreneur I applaud. I personally believe (and hope) that the ultimate competition to his company and risk to him and his investors will be via behavioral and “natural” changes vs competing “wonder drugs”. I would have liked to hear how he views this possibility. Please don’t misunderstand my admiration for his work – I believe drug therapies can save lives, improve health-spans and provide interim solutions on the path to find more reliable and durable nutritional/dietary solutions. (We face similar challenges while we develop both interim and more sustainable solutions in the CleanTech, Clean Energy and Climate Change space.)

  6. People here commenting about lifestyle, diet, blah blah blah clearly do not have clinical backgrounds, nor even a basic understanding about interindividual differences in trait self-control (~60% of the variance is heritable).

    It doesn’t take a genius to know that diet and exercise are going to help age-related diseases, good luck ever enforcing compliance though, it’s never going to happen. Go have a look at how jaded the average family physician is in regards to making lifestyle/diet changes, most patients do NOT listen or comply – it is a near futile endeavour.

    Yes, even if this patient’s sedentary lifestyle and high carb diet is literally killing them – these patients unfortunately will not change.

    Perhaps you could point to something like Valter Longo’s fasting mimicking diet as a way to address this compliance issue, but even then it still misses the point.

    Aging is by far the greatest risk factor for chronic disease and no amount of diet/exercise is going to change the final trajectory. To take Unity’s OA trial for example; telling a patient they just need to change their diet/exercise is unbelievably disrespectful to their suffering, especially when exercising is literally painful. These tools are simply insufficient to address aging – that is where drug development is necessary to target the underlying aging biology.

    I cannot wait until the aging biology field completely revolutionises medicine, we are ready for a Kuhn paradigm shift if these drugs successfully translate to humans.

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