Perspectives as Charles Brenner challenges David Sinclair on longevity claims

Professor Charles Brenner of City of Hope does great research, but I also applaud his efforts against longevity hype.

Recently, Brenner and James Timmons publicly questioned some of the work of Harvard Professor David Sinclair. It’s a notable case of academics intensely disagreeing in the public space.

Background

While it’s interesting, it’s also a somewhat unusual experience to see fellow professors going at it this way.

What’s going on with Brenner, Timmons, and Sinclair?

Before we get into that, I recently wrote about a critical article in the WSJ on David Sinclair’s longevity businesses. Check that out for some background. Also, note that I and many others have concerns about some of Sinclair’s statements, tweets, etc.

For example, Sinclair tweeted (now deleted) about supposed anti-aging dog treats, a tweet that was inaccurate and seemed like hype. Note that Sinclair’s brother is a leader of that dog treat longevity firm. Also, see my article on anti-aging tricks and treats for more on the canine stuff. This dog biscuit case highlights potential links between anti-aging hype and commercial aspirations.

David Sinclair Cell paper

Sometimes it’s hard to know what to think when professors go at it. In this case, I believe that Brenner and Timmons were correct in raising questions.

Here’s the original Sinclair lab Cell paper: Loss of epigenetic information as a cause of mammalian aging. You can also check out my initial journal club-style review of that paper here on The Niche.

I thought it was very interesting but speculative. The team conducted in vivo reprogramming in mice and claimed impacts on aging, proposing the “information theory” of aging. They also had a system for accelerating aging of the mice.

Note that this paper has now had a correction, providing some important additions.

Specific concerns from Charles Brenner and James Timmons

Timmons and Brenner sent a letter to Cell entitled “The information theory of aging has not been tested” about the Sinclair team manuscript. Among other issues, they raised concerns about cell death via p53 potentially confounding the results and weakening the main theory of the paper. Timmons and Brenner also noted some uncited work that should have been referenced in the paper.

These are valid concerns. The last paragraph of their letter challenges some of the main thrusts of the Sinclair Lab paper:

“The effect of Yamanaka factors on the epigenetic state of cells is well known,⁸ but the Cell paper’s highlights told readers that “aging can be driven forward and backward.” Their discussion concluded that “fortunately, it is now apparent that mammals retain a back-up copy of youthful epigenetic information that can safely restore the function of old tissues, akin to reinstalling software.” Moreover, their graphical abstract showed an old mouse on the right driven by OSK to a young mouse on the left. However, the paper showed no data on functional rejuvenation due to OSK treatment. Figure 7S shows the effect on the eyes of the tamoxifen-induced I-PpoI: the eyes are opaque in the I-PpoI mice but there was no functional characterization of OSK-treated iDSB mice. The Cell paper does not document any old tissue with restored function in any mouse and no data in support of restoring function were provided by Dr. Sinclair when requested.² Given their related manuscripts not being cited and appropriately cross-referenced, the issues around I-PpoI-induced cell death, and lack of demonstration of the major claims of the paper, we remain concerned about the validity of the published Cell¹ paper.”

Here is the subsequent response to this Brenner and Timmons letter from David Sinclair and his team, also in Cell.

Looking ahead on in vivo reprogramming

One of my specific concerns was that this Cell paper didn’t mention teratoma one way or another. You can imagine that introducing reprogramming factors in vivo could easily form iPS cells, which then go on to generate teratoma.

This should have been discussed in the paper even if they did not find teratoma.

I seem to recall tweeting to Sinclair to ask about teratoma in these studies and he replied that they didn’t see any. I’ll have to see if I can find that old tweet.

More broadly, the risk of teratoma is just one reason why I’m still somewhat skeptical of in vivo reprogramming having any imminent clinical importance. The trick is strictly to spark partial reprogramming and just get “younger” cells of the same fate, not iPS cells or some neoplastic intermediate like aggressive neural precursors. For example, if you conduct in vivo reprogramming on the liver, you want to get “younger” liver cells, not millions or billions of iPS cells in the liver. You also wouldn’t want abnormal, aggressive immature liver precursor cells that can grow tumors.  Since reprogramming works better in proliferating cells, in vivo reprogramming may happen more often in precancerous cells.

Sinclair isn’t the only one pursuing in vivo reprogramming. I’m curious to see future papers from both his lab and others. For instance, Juan Carlos Izpisua Belmonte, now at Altos Labs, has done important work in this area. Encouragingly, I haven’t seen him hyping the results.

Finally, note that Brenner also reviewed David Sinclair’s anti-aging book. I’ll end this post with the conclusion of that review, where Brenner really takes off the gloves:

“For scientific discoveries to be developed they need to be real but for books to sell, the stories just have to be good. The reach of Lifespan is a problem for the world precisely because a Harvard scientist is telling fictitious stories about aging that go nowhere other than continuing hype as legendary as anything in Herodotus.”