Roughly a decade of progress in biogerontology

Epistemic status: I'm stealing the idea from the lesswrong forums, as it may help me fight my perfectionism that stops me from blogging. This post is better than just brainstorming but not quite like a proper literature review. Regarding some of those fields, I have read hundreds of articles, whereas for others I have only my intuition as a (mediocre) biogerontologist. This post is subjective.

Roughly a decade of progress in biogerontology
I've been following different aspects of aging research for about a decade, on and off, with a particular focus on translational biogerontology. The optimist in me of course wished to see faster progress, but realistically speaking we have seen some real breakthroughs given limited funding and limited acknowledgment of aging as a treatable condition. While it is hard to say at this vantage point, it is possible that aging research has accelerated, altough I am not entirely sure if it grew faster than other biomedical research did in the last decades. For a similar take, Reason from fightaging has called the pre-2000 era the "lost decades" of aging research and it is indeed difficult to look back without feeling some anger at the many wasted opportunities. However, instead maybe we can look forward with some level of optimism.

If you are interested in earlier decades, this review by Arlan Richardson provides some good reading for the period between 1970 to 2020 (Richardson 2020) and for 1985 to 2010 there is one by Martin Brand (2011). Unfortunately, these are a bit American-centric.

Content
The big two: no surprises
Proliferation of mouse models and increasing quality of mouse work
Towards actual understanding: pathways and aging theories
The rise of non-standard models and comparative biogerontology
Translational studies - one step closer to the clinic
Clinical trials and regulatory framework - a bit better than nothing
The cool stuff: blood is back on the menu
The setbacks and the biggest disappointments

The big two: no surprises
In 2009 Harrison et al. found that the mTOR inhibitor Rapamycin fed late in life, extends the lifespan of quite healthy, well-husbanded mice. This was a breakthrough on at least two accounts. First, Rapamycin was the first drug to demonstrate robust lifespan extension in mice. Second, it worked in middle aged mice, which is the pre-requisite for widespread clinical application. It was also a great disappointment, because Rapamycin is already approved as an immunosuppressive drug and is known to be quite toxic. While we think that the beneficial effects of Rapamycin do not depend on immunosuppression, so far no one managed to successfully uncouple mTOR inhibition in different tissues and to come up with Rapamycin analogs (rapalogs) that aren't immunosuppressive.

The Rapamycin finding came from the NIA's Interventions Testing Program (ITP) and it was a surprisingly early hit in the life of this programme. The NIA ITP was set up to screen a couple of drugs per year in large groups of healthy mice to see if they extend lifespan (this is called a "cohort") and by now the ITP has been publishing yearly data for at least ten years. Although Rapamycin was confirmed in the second year, it remains the gold standard in the field. Only time will tell if that early hit was lucky or if murine life-extending drugs are really rather more common than expected.

Figure from Harrison et al. 2009: Rapamycin extends lifespan in male and female mice

It is difficult to pin the second big breakthrough of the decade to a single study, because senolytics were so long in the making, with several milestones along the way. However, as a translational gerontologist at heart, I have to say that the lifespan studies were the true breakthroughs, Baker et al. 2016 showed that the p16-mediated ablation of senescent cells extends mouse lifespan and Xu et al. 2018 found that dasatinib + quercetin can be used to remove senescent cells and also extend lifespan. One could argue that the lifespan extension by senolytics is more modest than by Rapamycin, which is true, but it feels solid enough to top the list. In particular, because senolytics would be more convenient from a regulatory perspective since they can be used intermittently.


Proliferation of mouse models and increasing quality of mouse work
The last decade has seen the emergence of many new genetically modified mouse models with extended lifespan. Currently "over 50 genes have been reported to increase the lifespan of mice" (Richardson 2020) while in 2009 we had around 20 or so genetic interventions (Ladiges et al. 2009) and in 2003 only seven to eight (Liang et al. 2003). (Please remember these numbers depend on the way you count and classify models.) What is more, I think we have recently discovered some very strong models with FGF-21 transgenic mice and c-myc haploinsufficient mice, although I am still waiting for independent verification of these two models.

On the topic of "strong" models: As others have pointed out, including Richard Spindler, we always had a problem with shoddy mouse studies. Thanks to the NIA's Interventions Testing Program and the higher prominence of aging research - a good mouse study gets you into Science, Nature or thereabouts - I would say the quality of research has greatly increased in the last decade.

Towards actual understanding: pathways and aging theories
We have to appreciate that within the last decade enormous progress has been made in understanding aging and we have taken important steps towards figuring out why some species or models age slower. Below follows an incomplete account of my personal highlights.

We made a lot of progress towards understanding pathways that underlie caloric restriction with the discovery of the H2S axis (Hine et al. 2015) and of FGF21 signaling (Zhang et al. 2012, Davidsohn et al. 2019). I am particularly excited about H2S as a basic glue that keeps together the biology of CR and CR-like states.

Now let us briefly review the aging theories that made good progress. A theory here means a set of concepts or ideas that are able to explain aging patterns of certain cells, tissues or organs (there is no single aging theory that accounts for everything). A good or useful theory should not be idiosyncratic; it should be applicable to more than one species, more than one cell type, etc. If a theory is vague, not actionable, or lacks good support from models that I consider strong (e.g. mouse KO and overexpression, comparative biogerontology), it will not make the cut here. Also, please excuse me if I miss something obvious or your favorite theory.

The multistress resistance theory came to replace the oxidative stress theory of aging because it makes sense as a "superset" that is actually supported by good data. Labs found that Nrf2 signaling is increased in long-lived species (Lewis et al. 2015) and that, in mice, knocking out Nrf2 attenuates the benefits of caloric restriction (Pearson et al. 2008).

The theory of DNA damage and aging is one of those theories that everyone knows to be right but that somehow has never any practical implications and turns out to be too difficult to study. I think the theory was buoyed by the data on multistress resistance and the fact that DSBs could induce senescence. Apart from that, we have mounting evidence from comparative biogerontology that DSB repair capabilities are higher in long-lived species and the work of Tian et al. (2019) is the culmination of over a decade of research on this topic. Jan Vijg writes very good reviews highlighting the accumulation and importance of DNA damage, yet I believe we are still lacking the smoking gun. Can we get mouse KOs that age slightly faster, not sick progeroid mice, to support the theory? Can we get transgenic mice overexpressing repair proteins that at least show segmentally slower aging? Can we have a concept to improve DNA repair in humans?

Epigenetic aging is still not that exciting because it is not actionable, although there is mounting evidence for the importance and potential reversibility of this problem (Hayano et al. 2019, Lu et al. 2020, Fahy et al. 2019). I am particularly impressed by the Hayano manuscript from the Sinclair lab linking accelerated aging, as measured by the frailty index, to a modest induction of non-mutagenic double strand breaks that screw up the local chromatin landscape - a tidy hypothesis and result that is almost too good to be true.

Even if epigenetic aging theories are in their infancy, epigenetic clocks are already among the most promising surrogate markers under development (Thompson et al. 2018, Horvath et al. 2013, Bell et al. 2019) so I feel the whole concept is worth putting here. On the topic of surrogate markers and other pre-requisites for basic-translational and clinical research, I am VERY pleased with developments like standardized frailty indices, systematic pathology grading, Stephen Spindler's efforts to catalogue and criticize bad mouse husbandry and the UM-HET3 mouse developed at the NIA.

The inflammation theory was strengthened due to the CANTOS trial in 2017, the link with senescence and relatively strong longitudinal and observational data (e.g. Li et al. 2017 on IL-6 and mortality).

Autophagy is strengthened by the Rapamycin data (Unnikrishnan et al. 2020), cross-species data and a couple of new mouse models over-expressing autophagy genes (Fernández et al. 2018, Pyo et al. 2013). As far as the comparative data is concerned we know of increased autophagy in long-lived rodents (cross-species; Rodriguez 2018) and fibroblasts derived from long-lived mice (intra-species; Wang and Miller 2012). This may also be the right place to explain a couple of biases at play, that make the data difficult to interpret. We scientists have the habit of discounting data that is inconsistent. There are plenty of mouse models that show at best tiny lifespan extension like Metformin, Spermidine or Resveratrol and all these substances, at various times, were suggested to operate through autophagy. Does this mean autophagy is not important to longevity? Or is it a minor, albeit necessary, player? Or maybe this actually strengthens the hypothesis because all three of these have at least health benefits, if not longevity benefits? (Please note, I do not want to single out the autophagy field, as these problems are quite universal in biogerontology because the questions we ask are hard.)

Other pathways, theories and ideas were disappointing (which does not preclude a resurgence in the future) including but not limited to: the telomere field (although the Nobel prize in 2009 can be credited for giving us good publicity), advanced glycation endproducts & tissue cross-linking, extracellular matrix aging (say e.g. calcification and elastin fraying), mitochondrial aging (lots of data but nothing that strikes me as actionable and no overarching theory), the study of extreme longevity in humans (GWAS studies), extracellular junk (amyloidoses and the eternal failure of the amyloid Alzheimer's hypothesis), intracellular junk (lipofuscin etc.).

Genomics and other omics has been a mixed bag, and a let-down for a long time, but I would say that with the advent of RNAseq and cheaper next gen sequencing we saw some real progress, often at the hands of the Gladyshev lab (e.g. his RNAseq work; Fushan et al. 2015). Proteomics seems to be quite a bit harder both a the single-cell level and across species, but we have seen some promising results as well. Epigenetic clocks would also not be possible without these technological advances. Currently these use array technology, but sequencing based methods are in the works. Interestingly array based technologies never really caught on for transcriptional analyses in biogerontology, but seem to do OK in the methylation field.

The rise of non-standard models and comparative biogerontology
Aging researchers are diversifying the animal models they use. Although this may be merely a consequence of more funding to go around, it is still a wise decision. The reasons why canonical models have become the standard in all biomedical research is also a disadvantage for biogerontology. These models are convenient because they breed quickly and thus have a short lifespan. On top of that, at least with lab mice, there may have been selection for fast growth and thus obesity and metabolic morbidity which will exaggerate the effect of anti-aging interventions we test. Mice are not just short-lived in absolute terms, they are also exceptionally short-lived in relative terms, when you consider their size. Thus the need for other models is obvious.

Personally, I find exceptionally long-lived models somewhat more valuable because we already have enough short-lived ones so I am not overly excited about killifsh research. Whales, naked mole rats, turtoises, bats and parrots, on the other hand, are amazing additions to our gerontologic armamentarium. However, we have to keep in mind that their use is still very limited. For example, I do not think any particularly long-lived non-standard animal models are actively bred in academic labs, besides naked mole rats (pioneered by Rochelle Buffenstein). So we often have to resort to zoosecologic studies or bioinformatics if we want to look at non-standard models.

The field of comparative bigerontology saw lots of incremental improvements. In fact, the above mentioned non-standard models are often used in large, comaprative studies that look at multiple species at once. In addition, not long ago we saw the first issue of the AnAge database (de Magalhães and Costa 2009 [as far as I can tell]) and more attention to scientific rigor with phylogeny- and bodymass-correction becoming more or less standard in the field, but unfortunately demanding quite large sample sizes. This is of course necessary because many traits correlate with body mass (e.g. nose and scrotum size) and body mass itself correlates with lifespan, which could lead to some very awkward results.

Translational studies - one step closer to the clinic
Almost forgot this one for some reason. The fledgling Dog Aging Project by Matt Kaeberlein who is "hoping to treat 500 dogs over a 5-year period with Rapamycin" in order to prove that the mouse data translates to other organisms. The sample size seems about right, maybe even low, given that this will be much less controlled because these dogs live with their owners. The sample size in the original Harrison study was ~300 rapa-treated mice across two genders. I believe we will look back on Kaeberlein's work one as one of the most important studies in the history of modern biogerontology (whether it fails or succeeds).

Genetics of (human) aging: hardly any progress
To put it bluntly"despite a plethora of studies, only few variants ([e.g.] in the APOE, FOXO3A ...[genes]) have been successfully replicated in different ethnic groups.." and the initial findings on these genes generally date back to before 2010. If we are a bit lax maybe we can put FOXO3a into the current decade with studies like (Anselmi et al. 2009Wilcox et al. 2008, Kuningas et al. 2007). Unfortunately, I am not an expert in this field but overall I am disappointed by the progress in the genetics of human aging.

To be fair, the genetics of model species can be credited with launching the modern era of biogerontology between 1990-2010 (Richardson 2020, Martin 2011) with e.g. the seminal work on Prop1 in mice and daf-2 mediated life extension in C. elegans.

Clinical trials and regulatory framework - a bit better than nothing
As always dermatology is undervalued. In the past we have seen approval of retinoids for photoaging as a regulatory milestone. Similarly, these days some of the most convincing Rapamycin data has come from dermatologic applications (Chung et al. 2019).

As far as the push to have aging defined as a disease is concerned, the TAME (metformin) trial takes the cake as the most daring endeavor despite its shortcomings (Konopka and Miller 2019). The aim is to enroll around 3000 "healthy" people between 65 and 79 years of age, although it seems like they will be allowed to have, or even be selected for, significant age-related comorbidities (apparently including prediabetes, Glossmann and Lutz 2019)

[as per the TAME webpage:] The TAME (Targeting Aging with Metformin) Trial will establish a clinical trial to provide proof-of-concept that aging can be treated, just as we treat diseases.

We hope the FDA will approve aging as an indication, to signify that aging can be “treated.” In medical terms, an “indication” for a drug refers to the use of that drug for treating a particular condition. 

One significant point of progress is the focus on multi-disease endpoints in the TAME trial ("myocardial infarction, congestive heart failure, stroke, most cancers, dementia, and death, but not diabetes [or frailty]"). Although opening the dialogue between the TAME team and the FDA is certainly a form of regulatory progress, for a long time it was not entirely clear if TAME could be fully funded and when they would start recruiting patients (Glossmann and Lutz 2019), but it seems these problems were finally resolved towards the end of 2019.

In parallel it feels like there has been a slight but noticeable uptick in the involvement of pharma & biotech companies trying to develop therapies for age-related diseases, suggesting the field is now more mature (see e.g. Magalhães et al. 2017, Partridge et al. 2020). At a quick glance, however, I could not find any statistics for the numbers of aging-related biotech companies over time and I was informed that there is still little opportunity for "regular" people to invest in this field outside of venture capital.

Treatment of age-related diseases & biomedical research more broadly
Ok, admittedly this is a fuzzy category so I will keep this very short. What is even the difference between normal biomedical research and pharmaceutic research on age-related diseases? Nevertheless, it is worth pointing out a couple of highlights. There has been good progress against cancer, one of the prototypical age-related diseases. For example, the HPV vaccine was approved around 2007/2008 and recently vaccines covering more HPV types have become available (9-valent human papillomavirus), making it one of the safest primary prevention strategies to reduce cancer incidence, which will be needed to slow human aging. Then there is checkpoint inhibition for cancer, especially useful for melanoma. 

Aspirin seemed promising for a while against cancer but appears to have failed in primary prevention trials. Since the anti-aging crowd has some overlap with body builders, biohackers and supplement believers it is reasonable to point out that supplements continue to underperform because primary prevention of diseases is difficult (e.g. vitamin D recently flunked in a huge study). There is also little public health progress against cancer and premature aging from obesity, smoking, alcohol and ultra-processed foods.

Then of course we have benefitted from all the other biomedical research like *omics and CRISPR. However, if I were to highlight research most relevant to aging it would be gene therapy. Eventually it will play a role. Meanwhile there has been small but steady progress with actual FDA approvals trickling in from 2017 onwards but also highlighting the tragedy of targeted therapies: small markets make them exceedingly expensive. 

The cool stuff: blood is back on the menu
The whole "young blood" idea materialized around 2005 with the work of Conboy and Rando on heterochronic parabiosis in mice but most of the interesting work followed later (see e.g. Yousefzadeh et al. 2020 for a recent study in the field and a brief review). The idea was that transferring the blood or some circulating factor from young animals to older animals could rejuvenate aspects of their physiology. Over the last decade the idea has matured, yet many questions remain unanswered. We still do not know for sure if it is the transfer of circulating (stem) cells that is beneficial (what is best plasma, serum or whole blood?), the transfer of circulating factors or dilution of existing factors in the old animal as put forward recently, etc.

What is more I am always feeling very queasy about Ivy League labs publishing mouse studies with such vague outcomes of segmental healthspan. Remember, the pressure is really high on both grad students and PIs to produce results, their funds are almost endless while segmental healthspan studies are much cheaper than lifespan studies and the rewards are huge in the form of grant money and prestige. Without imputing malice we have to consider problems like p-hacking and publication bias. It might have been Feynmann who said "The first principle is that you must not fool yourself and you are the easiest person to fool."

To address this problem, we need to establish standardized measures of healthspan (discussed above) that will become mandatory if you want to publish in high impact journals and ultimately pre-registration for all longer and larger mouse studies, which also includes segmental healthspan studies. However, I am not intending to ban unregistered mouse research. Instead I would like to see a clear distinction between pre-specified primary outcomes and explorative analysis. Maybe the problem is easier to understand if we look at a real world example. Let's imagine a mouse liver weighs 2g, and we can easily perform experiments on <100mg pieces, including biochemistry and histology, so you could end up using those tissue samples for >20 experiments by different students and postdocs (or sending them to >20 collaborators). Often when the experiments fail people will say "Oh maybe I messed up", "yeah this was just speculation and hypothesis testing, let's focus on something else", "if I publish this null result it will not help me to get funded and I have a responsibility towards my grad students and postdocs to bring in money", "dear lab book, today I did not feel well and performed no experiments (my PI scares me)". It is way too easy to fool yourself, but ultimately all of this is massive p-hacking and leads to the inflation of published results.

Yes, I do have a particularly pessimistic view of the young blood field given the continued controversies.

The FeAst study (Zacharski et al. 2008) was a trial of blood-letting and it fits nicely with the young blood theme. That is, the idea that old people have an accumulation of something harmful in their blood, or a lack of something youthful. The study showed that blood letting reduced cancer incidence with no significant benefit on cardiovascular disease. Not at all absurd, it is still one of those studies that were just too good to be true and concerns have been raised about the results. Even if we are optimistic, one has to admit that cancer was a secondary endpoint and cardiovascular disease a primary endpoint in that study.

I am generously including FeAst and all the progress on the "young blood" idea in my 10-year window. 

In summary, we can learn that the modern day vampire should continue their blood drinking diet, but would be well advised to eschew whole blood and switch to a leaner diet of young plasma. As absurd as this sounds, perhaps it is not that far from the truth. Maybe in a not too distant future middle aged and young men will donate blood to increase the supply of blood products while reducing their risk of disease! One can envision even more elaborate schemes depending on how the science develops.

The setbacks and the biggest disappointments
These are also easy. First of all, there is the CR controversy in mice and primates. One major study found that CR shortened the lifespan of several heterogenous, but still inbred, mouse strains (Liao et al. 2010*). The methodological shortcomings of the Liao study are not enough to invalidate it, which is extremely worrying and the biogerontologic community has spent little time to address the elephant in the room preferring to gloss over the issue.

Less worrying yet also disappointing is the data from the ongoing primate studies showing that the CR benefits may be exaggerated and instead CR simply reduces pathologic adiposity (Colman et al. 2014, Mattison et al. 2017). Why are these studies problematic? I am sorry-not-so-sorry to say but all of the primate data is a clusterfuck** and we really cannot blame the researchers, because the funding structures are not set up to handle basic studies that last 40 years, nor did they have the resources and knowledge we have now when they designed the studies. Studies now known to be methodologically very weak and underpowered. However, we've not yet had the last word on the issue as the studies are still ongoing.

Considering that half a century of research rests on the assumption that CR works to a reasonable extent, you better believe this was the disappointment of the decade.

There was also a lot of hype that wasted quite a bit of resources which includes resveratrol and to a lesser extent polyamines. You can see the impact the hype had at the NIA ITP, whose reviewers accepted not one but actually three different doses of resveratrol to be tested in mice.

Finally, I feel like Rapamycin and senolytics have not generated as much excitement as they should have and the push towards human clinical trials and towards lifespan studies in long-lived species has been too slow. This brings me back to Reason's blog post: we are still too slow, wasting too many opportunities. There are millions of volunteers who would take part in a Rapamycin study, or any other anti-aging study, and we are not tapping that potential.

References & comments (selection)
*another study found that CR had only modest non-significant benefits in wild-derived mice but this was earlier (Harper et al. 2006)

** to explain the problem in a bit more detail: I am enraged that researchers have squandered a lifetime opportunity here. These studies are so unbelievably important and yet so underfunded. Carrying out this work takes literally half a human life-time, around 40 years, and the world could not be arsed to make sure we had enough healthy, well-husbanded, lean monkeys in the study and a graded CR regimen? And again, we the researchers can't really do anything about it if we do not get the funding, but this does not make the story any less disappointing.
Also please remember, the studies are not negative but they are also not as positive as they should be if CR translated well to the primate model. Most importantly, there is the issue of weight across the studies with most of the reported benefits seen in the heavy animals. In clinical terms we could say, maybe the control monkeys have a BMI of 25 and the intervention monkeys of 21, this makes them "lean" or metabolically "normal" but is not similar to being underweight which is often associated with premature death in epidemiologic studies (This is an analogy, CR data does not trivially translate to BMI data, although there are parallels.)

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Kommentare

  1. Hey, saw this on Guzey's newsletter. Nice review!

    Few questions:
    1) "Labs found that Nrf2 signaling is increased in long-lived species (Lewis et al. 2015) and that, in mice, knocking out Nrf2 attenuates the benefits of caloric restriction (Pearson et al. 2008)"

    Having not read the original papers (or being familiar with the field), I'm having trouble reconciling these 2. Caloric restriction is a method of extending lifespan, but is there a more fundamental connection between CR and lifespan extension?

    2) "The inflammation theory was strengthened due to the CANTOS trial in 2017, the link with senescence and relatively strong longitudinal and observational data (e.g. Li et al. 2017 on IL-6 and mortality)."

    Can you expand on this? I'm always very curious to understand what exactly inflammation is, because it's such a broad term.

    3) Does autophagy = mitophagy, or is a broader term? It's very related to Parkinson's, which is an interest of mine, so I'd be very curious.

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