Exploring the Frontiers of Science: Breakthroughs, Funding Challenges, and Replication Crisis with Alaattin Kaya during The Aging Science podcast by VitaDAO
Check out the podcast here.
We talked about recent breakthroughs in the field, the difficulties of getting funding for risky and novel research, funding agencies, “fishing expeditions”, the importance of overexpression genetic screens in aging research, novel mechanisms of action, and the replication crisis.
We also talked about yeast as a model organism and had a clear consensus:
“Of course, yeah, [it’s] everybody loves yeast.” (Alaattin Kaya)
It was a fun podcast! Since we really liked Alaattin’s overexpression screens (see below for more) we want to help him fund his amazing research. So if you know of any philanthropists or funding agencies that are willing to fund moonshots in aging research, please do reach out to us or directly to him.
Let me give a bit of scientific background on our main topics before we start. If you are quite familiar with this topic you can also just jump right into the podcast. Even if the below explanations are a little handwavy, I do hope they will be useful.
Overexpression of essential genes in yeast screens
The idea of genetic screening in model organism is quite simple. Models like yeast, worms or flies are less complex than humans, have a short lifespan and reproduce quickly making them facile models to study aging. Researchers can test thousands of compounds or change the expression of thousands of genes in a matter of weeks, in order to see whether these extend lifespan. Often they will find genes or pathways that are conserved between species, meaning they could also work in humans. One famous example of a conserved pathway is the Insulin/IGF-1 signalling pathway. Cynthia Kenyon and others discovered and validated this pathway in worms, showing that loss of daf-2 — which is related to human insulin and IGF-1 — leads to drastic lifespan extension in the worm. The importance of this pathway was later confirmed in mice.
Essential genes are those that are necessary for the survival of an organism. It stands to reason that these are important and often involved in tissues maintenance or repair. Given that “damage theories” of aging are well supported this makes essential genes attractive targets to study. What is more, essential genes will be often conserved between species. So if we found an essential longevity gene in yeast, for example, it would be more likely to do the same in humans than a non-essential gene.
Intriguingly, during evolution the duplication of (essential) genes often yields genes with novel functions, some of which are important for aging. Indeed, I worked myself on one such gene family. We suggested that cytoprotective metallothioneins might have undergone duplications that allowed for higher expression in longer-lived species (Pabis et al. 2021). While the evidence is not perfect, it is quite striking that humans have a dozen metallothioneins while short-lived mice have only three and worms have two metallothioneins. Alaattin mentions another example of an important gene duplication during the podcast.
Longevity probably evolves via gain of function (and change of function) rather than loss of function, which we usually study in the lab.
In contrast, essential genes are hard to study, because knocking them out, as is often done in genetic screens, would be lethal to the organism. Therefore most genetic screens focus on the knock-out of non-essential genes and in pharmaceutical screens inhibitors are easier to find than activators. Here is where Alaattin’s idea comes in. He decided to study the over-expression of essential genes to test whether these promote longevity in yeast, which are the perfect model for this since you can overexpress genes using so called plasmids.
If you want to know more about the project, Matt Kaeberlein explored this topic in his ARDD talk titled “The dark matter of bio-aging” (5). For those who are keen to read the paper itself, Alaattin’s preliminary work funded by Impetus grants, among others, has been published (Oz et al. 2022).
We scientists often call such screening experiments jokingly “fishing expeditions” because you never know what you will dig up. While a valid criticism of this approach, it is not a convincing one. During the podcast we discussed how reviewers take this criticism too seriously, favouring work with a clear mechanistic rationale instead and how this affected Alaattin’s research.
Lack of novel mechanisms?
“I think in aging everything is controversial at this point to be honest” (Alaattin Kaya)
Without getting into too much detail, reviewers who decry fishing expeditions could not be more wrong. While, yes, we do have some very outlandish ideas in the pipeline (reprogramming, parabiosis), by and large the field is almost exclusively dominated by quasi caloric restriction(CR)-mimetics. Treatments that target anabolic pathways and slow growth in one way or another are currently the only interventions that lead to robust mouse lifespan extension. Even worse, we still do not understand aging well enough and hence we need to feed the translational pipeline from the bottom up with the most novel and outlandish things we can find during our fishing expeditions — if we want to make any progress against aging in the longterm. Overexpression screens in model organisms would be great for that.
Bio and research focus — Alaattin Kaya
Alaattin is a young investigator who recently started his own lab at the Virginia Commonwealth University. He worked as a PhD and postdoc under the great Vadim Gladyshev and is a close collaborator of Matt Kaeberlein. His focus is on using yeast as a model to study basic mechanisms of aging. On his lab webpage Alaattin makes a good argument for using yeast in aging research:
“Current evidence suggests that many of the aging mechanisms and related genes are conserved among eukaryotes, from yeast to mammals. Each model system provides key advantages and challenges. Due to a variety of factors — notably including ease of genetic manipulation and a physiology similar to that of humans — the mouse has become the pre-eminent mammalian model organism in aging biology. However, in light of the high housing costs and relatively long lifespan of mice, large-scale unbiased screening to identify anti-aging medicines is not feasible in this organism. With the realization that many aging-related pathways are evolutionarily conserved, even among widely divergent species, short-lived invertebrate models have instead been employed for such screening.”
You can find more information under kayalab.org or on twitter @akay_lab.
1. Evidence that conserved essential genes are enriched for pro-longevity factors.
Oz N, Vayndorf EM, Tsuchiya M, McLean S, Turcios-Hernandez L, Pitt JN, Blue BW, Muir M, Kiflezhgi MG, Tyshovskiy A, Mendenhall A, Kaebverlein M, Kaya A. (2022) GeroScience https://doi.org/10.1007/s11357-022-00604-5
2. Kenyon, Cynthia, et al. “A C. elegans mutant that lives twice as long as wild type.” Nature 366.6454 (1993): 461–464.
3. Malavolta, Marco, and Kamil Pabis. “Elevated metallothionein expression in long-lived species.” Aging (Albany NY) 14.1 (2022): 1.
4. Pabis, Kamil, et al. “Elevated metallothionein expression in long-lived species mediates the influence of cadmium accumulation on aging.” GeroScience 43.4 (2021): 1975–1993.
5. Matt Kaberlein at ARDD2022: The dark matter of bio-aging
Kaya, Alaattin, Alexei V. Lobanov, and Vadim N. Gladyshev. “Evidence that mutation accumulation does not cause aging in Saccharomyces cerevisiae.” Aging cell 14.3 (2015): 366–371.