From the flatlands to the highlands: Neurobiology and Neuroendocrinology of Aging conference (Draft)

When I arrived from arid Vienna at the "Twelfth International Symposium on Neurobiology and Neuroendocrinology of Aging" I was greeted by rain, fog and mist. The alps are so beautiful when they are covered in milk:

And here's our venue:

Which was located in Bregenz, part of which is pictured here:

Although, the major topics of the conference were senescence and neurobiology, the talks I had been particularly looking forward to were Christian Sell on mitochondrial stress, Bill Sonntag on IGF1 and Joseph
Kemnitz on CR in rhesus monkeys ("WNPRC cohort"). It's noteworthy that the name of the conference is a little deceiving, because a large number of talks were more general in nature.
Primarily, I was interested in the Sell talk because I work on mitochondria. I also disagree with Sonntag to some extent, so that is why I was interested in his talk. Since I had some unanswered questions about the degree of restriction in the rhesus monkeys and some methodology-related question, I wanted to take the opportunity to ask Kemnitz about these issues.

Regarding mitochondria I was also wondering about the relevence of mito-nuclear signalling.

Other interesting speakers included: Jim Kirkland, Julie Anderson and others on senescence, Arlan Richardson on rapamycin and Alzheimer's, as well as John Richie on methionine restriction. I am familiar with the work of all the above speakers except Richie.
Methionine restriction is certainly worth a second look, since there are still so many unanswered questions, just to give some examples: a. How does it differ from CR (are there any good pair-feeding studies?), b. Does mild met moderation work, c. How is it related to BCAA moderation/restriction and restriction of essential amino acids.
Regarding rapamycin I am mostly interested in translational experiments and clinical trials as these would finally provide proof of principle that this paradigm can be applied to humans.

Finally, Amy Wagers was going to talk about parabiosis experiments, which is a technique to study systemic influences on aging (here's a recent example of parabiosis and neurocognition).

Below, I will highlight some noteworthy talks, or take-home points, but obviously I will have to leave out crucial unpublished data.


George Roth, now working in industry, once principal investigator (PI) at the NIH, showed patent based data on mannoheptulose as a CR mimetic. In particular, beneficial effects on sarcopenia in dogs. Interestingly, I never heard this before. This CR mimetic does not get much press.
Buerkle gave a surprisingly insightful talk about biomarkers of aging full of unpublished data so I can't go into any detail. Let's just say they found markers that hardly anyone expected. And they were quite successful with their project.


Johnson & Andersen. Brain senescence remains largely unexplored and even non-proliferative cells like neurons can senesce. A powerful model regularly used is the linkage of a senescence associated promoter or gene to an inducible, toxic enzyme e.g. p16-TK fusion, which allows ganciclovir mediated ablation of senescent cells.
One question that remained unanswered was how we could proceed to ablation in humans.
Kirkland gave the clearest and most adept talk on senescence. He emphasized, how senescent fat cells may drive inflammation. JAK-STAT signalling is involved in this, some inhibitors are being investigated he explained. Additionally, senescent cells seem to have increased mTOR signalling. When asked, he mentioned that studies on ablation in healthy animals are ongoing. And studies showing decreased adipose senescence in dwarf mice have been recently published by Kirkland and coleagues.
I never gave much (teleologic) thought to the issue of senescence, but from an evolutionary perspective it makes sense. If senescent cells do not affect tissue function within a normal life span, there is no selection pressure for efficient removal mechanisms.
Niederhofer claimed that progeroid models are good models of aging. I disagree, although, I have been convinced that these models are better than I thought. Additionally, she tried to link her model to the vicious cycle hypothesis of mitochondrial aging, which most people in the field consider refuted. Perhaps I misunderstood her, however.

Sonntag made a good point about our need for adult-onset GH deficiency models and our lacking understanding of IGF1 biology, e.g. what role does autocrine IGF1 play? He reminded me how ambivalent the data regarding IGF1 and neurogcognitive function and decline is, though, he generally mentioned the studies favouring high-normal IGF1.
I noticed that some people consider him somewhat biased in favour of IGF1. I'm not disagreeing.

Sell found that ROS and aging stimulate mTOR and he seemed to implicate mitochondrial.


Othman Ghribi made a few interesting points about oxidized 27-OH-Cholesterol (27OHC) as a common cause for Alzheimer's and Parkinson's disease e.g. by increasing synuclein transcription. He emphasized the importance of oxidative stress, even though, 27-OHC is also produced via enzymatic reactions. I agree that there might be something to it, but it is important to remember that most antioxidant studies have failed to show effects on aging or neurocognitive decline in humans.
A speaker noted that the oxidative stress theory has a cosmic beauty: "you breathe, you die". That's part of the appeal. Well said.
Another thing I learned: the Tau-Amyloid dispute is jokingly called the dispute between Baptists and Taoists.

I can't comment on the talk by Andrea Stolznig, about nasal microglia delivery, not really my field. The idea is that they can chew up amyloid plaques. When asked, she did mention that they aren't completely sure whether they phagoytose amyloid or just secrete some beneficial factors.
Additionally, I found out that she was funded by "crowd funding"(?) and/or the "Longevity Forum"(?). That's awesome. These funding strategies are becoming more and more useful for pilot work.
Richardson gave a 'special presentation' on rapamycin. As expected, the talk was quite worthwhile and a little more controversial than expected. He mentioned that there's now a number of long term studies on Rapa and age-related diseases and they're almost uniformly positive. What really amazed me was that he thinks rapamycin may work without affecting stress resistance, but he feels like that's a preliminary statement (check the new paper PMID: 24409289). This idea seems extraordinary, because Rapa would be expected to enhance stress resistance via autophagy.
The most controversial part were his statements - almost? - downplaying the (immunosuppressive) side-efects of Rapamycin. It's certainly worth taking a second look at Rapa side-effects now that there's so much renewed interest in the drug. Some healthy people already started taking Rapa, but I always thought the immunosupression was quite considerable.


Just a few notes about the Kemnitz talk. More about the whole controversy can be found here. Kemnitz announced that the NIA and the WNPRC group are going to work together more closely in the future. Rhesus monkeys living outdoors, but still protected have a shorter lifespan than those kept in the lab. The more "wild", the shorter the lifespan apparently. Adult animals did not like playing around in the cages so no enrichment was provided. Overall, it seems like the a lack of enrichment and psychological diseaeses are very unlikely to have affected the animals in a negative way.
The investigators at WNPRC tried pair-feeding the restricted animals but would have had to drastically cut calories and they feared harming the animals.
Overall, he gave a few reasons for their choices, but it was clear from the talk that the NIA cohort would be more relevant to healthy aging as these animals ate less than WNPRC animals and their controls ate less than "historic controls".
Methionine restricted animals are quite small yet eat almost as much per animal as non restricted animals. This is one of the reasons why today we consider MR distinct from dietary estriction (CR/DR). Interestingly, they even have (slightly?) increased body temperature. The latter was thought to play a role in aging and cancer, which it might, but it's not an attribute preserved among all models.
Interestingly, MR did not have profound effects on DNA methylation.
We're still lacking dose-response studies of MR. Richie is also working on controlled trials in humans and considers them feasible. I guess we have different definitions of these words. When I said they're not feasible, I meant at the population level. And there's really no way to do this. According to his studies a met-restricted diet is a severely limited vegan diet. In the real world only a select few elite dieters can maintain a regular vegan diet! MR would need to be maintained for decades as well.
Mitchell found that acute dietary, methionine or protein restriction, depending on the study, increases resistance to trauma/stress - like surgery. Here it is important to note that restriction is severe and stops at the onset of surgery. This is quite interesting since there is some evidence that CR puts one at risk for some types of infection and might affect wound healing or recovery from trauma.
Mitchell was able to link many of the benefits to H2S signalling, but the jury is still out if you ask me, how much this pathway contributes to other CR effects.


Andreas Simm talked about Advanced glycation endproducts and aging. As expected, his group found a link to arterial stiffening, but surprisingly AGE-crosslinking seemed to protect from cancer in some studies. The idea ocurred to me that crosslinking could initiate cancer development, but promotion/progression would be lower through a stiff extracellular matrix.

Studies parabiosis in her group. If you link the blood supply of an old and a young animal it's called heterochronic parabiosis which is of interest to gerontologists. The list of (heterochronic) parabiosis benefits is long. They include reversal of heart hypertrophy, improved neurogenesis and improved strength and endurance. On the other hand, the young animals can lose some functionality.
Importantly, one of the factors they identified as responsible for this phenotype is the myostatin homolog GDF11. Myostatin might be expected to be catabolic and detrimental she mentioned, but I know that in reality the catabolic pathways are usually beneficial to tissue health and maintenance (think, CR and rapamycin for instance)
She noted that controlling for physical activity and other physical factors is hard, so they developed "sham parabiosis".
I heard of parabiosis before this talk, but never read up on it, so this talk was my conference highlight. The audacity and the elegance of the parabiosis approach is unrivaled. The translation into the clinic appears almost trivial in their hands. Wagers looked so young for a principal investigator and she's such an amazing speaker.