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

KEYPOINTS

• 01

  David's framework: aging is flexible, nature has 'control knobs', and some can be turned

  David, co-founder of Unity Biotechnology, points to similar creatures with very different lifespans. A hard clam lives about 40 years, while an ocean quahog has been aged at more than 500, roughly a 12-fold gap. Mammals range from shrews living under a year to bowhead whales, and rodents from field mice living two to three years to naked mole rats. Since the biochemistry is shared, he reasons that lifespan must be set by adjustable mechanisms.

• 02

  The first knobs discovered were insulin/IGF-1 signaling and calorie restriction

  Cynthia Kenyon's daf-2 work in roughly one-millimeter C. elegans worms doubled lifespan by impairing one gene, a 'mind warp' when aging was seen as passive decay. David cautions that worms are a weak model; analogous receptor knockdowns in mice give far less longevity. Clive McCay at Cornell first extended rodent life with calorie restriction in the 1930s. David believes rapamycin and calorie restriction work through the same knob, mTOR.

• 03

  Other candidate knobs include young blood, mitochondria and the methylation clock

  Experiments joining young and old animals date to the 1970s, which David notes is 'not exactly an optimal way to live.' He calls the methylation clock an area of intense debate. He uses the analogy of a vinyl LP, whose grooves wear down with each play, for how living itself might degrade the epigenetic record.

• 04

  Senescence is an anti-cancer emergency brake you don't want to remove

  Mice engineered so they can't make senescent cells are born normal but are full of tumors before reproductive age. Unity's approach leaves the brake alone and clears cells only after they have permanently stopped dividing. Even in a single dish of identical irradiated cells, some die and about 99% of survivors become senescent, and nobody knows why cells choose one fate or the other.

• 05

  The damage comes from what senescent cells secrete

  Senescent cells are only a small minority of cells, yet they can harm their neighbors through an inflammatory secretory profile, known as SASP, that co-founder Judy Campisi described in 2008. Campisi also found the first in-vivo marker of senescence around 1995. Leonard Hayflick overturned the dogma that cells divide forever in 1961, after earlier cultures had been contaminated by fresh cells in their feed.

• 06

  The company rested on four questions answered in parallel

  The questions were: do senescent cells drive natural aging, can clearing them reverse a modeled human disease, can drugs selectively kill them, and will it work in humans. The 2011 Mayo Clinic paper from Jan van Deursen's lab got David to meet within 72 hours. A five-year natural-aging study published in 2016 was 'the trigger' to go public about Unity's work.

• 07

  Osteoarthritis became the first target

  David calls osteoarthritis 'the primary reason it hurts to be old.' He says off-the-shelf pain models are irrelevant, so Unity used Jennifer Elisseeff's ACL-transection model at Johns Hopkins. Clearing senescent cells, genetically or with drug, reduced pain and regenerated cartilage in mice. In humans, senescent cells hover around 1–2% even in osteoarthritic knees, but their number scaled with disease and pain.

• 08

  Phase 1 knee data were striking but small

  The trial enrolled 48 patients, randomized 3:1 to drug or placebo across six dose levels of about six patients each, with a single injection followed for three months. Pain fell in a dose-dependent way and hadn't returned at three months. At the top dose, pain dropped from about 6.2 to just over 1 on a 0–10 scale, mostly within two weeks. David stresses the small numbers and the large placebo effect seen with knee injections, and warns against comparing results across trials.

• 09

  Clearing senescent cells delayed cancer onset rather than changing its prevalence

  In mice cleared from midlife until death, about 85% still died of lymphoma, but it appeared roughly 30% later in life, matching about a 30% lifespan extension. David calls this a phase shift of chronic disease and admits nobody knows why. The same mice kept 41% more intervertebral disc volume.