Samstag, 13. Juni 2015

What's hot in Aging Research? (2015 List)

I. Which interventions could produce a life-extension breakthrough in the next decade or so? (Short Term breakthroughs)
II. Which interventions hold promise, but are a little more speculative? (Mid Term breakthroughs)

Starting from now, I would like to review this question annually or every two years. In my analysis I'll include interventions, drugs, diets, etc. that could have a large and meaningful effect on aging or any of the major age-related diseases. From a methodological point, the answer must consider: A. effect sizes and B. plausibility (how advanced is the science?). Aspirin is an example of an intervention with high plausibility, but small effect size, since the effects are limited to cancer prevention. In fact, even if Aspirin reduced cancer incidence by 10-50% this would only result in 1 or 2 years added to the average human lifespan.

The answer to this question is personal opinion to some extent. To be as objective as possible I tried to track down reviews highlighting "important" research (3-6).

How can we make quick progress with so little understanding?
I believe there are plenty of low-hanging fruit á la calorie restriction (CR). These are interventions that would reduce lifespan in the wild, but increase it in captivity (e.g. slowed aging associated with modest immunosuppression). Nevertheless, plenty of controversy still surrounds CR demonstrating that even the low-hanging fruit in biogerontology may be quite hard to pick.

I. Short Term Horizon

Rapamycin

The only drug that could be realistically used to slow aging in the near future. We are still awaiting some more safety data and breakthrough studies e.g. late-life interventions in dogs or small primates. One advantage: plenty of human safety data exists on this drug.

Calorie Restriction and CR-mimetics (short or mid-term?)
Yes, the evidence supporting CR is strong, but it will be impossible to implement on a population level. So called CR-mimetics could be used widely, but are still very far away. However, I do expect that some of the CR controversy will be resolved within a decade (e.g. does it affect lifespan or only healthspan in primates, c.f. ref. 3).

Senescence
Research in this area holds promise for late-life rejuvenation and functional improvement.

Parabiosis and circulating factors
This procedure will help to identify circulating factors that play a role in aging. Even though the recent controversy regarding GDF-11 is a minor set-back (1). Also, human studies are still somewhat far away, unfortunately.

Iron dyshomeostasis (chemoprevention)
The FeAST trial suggests that iron has a massive influence on carcinogenesis and hence phelobotomy prevents cancer. On the other hand, only weak evidence links iron with aging so far, but chemoprevention alone would be a good start.

Aspirin (chemoprevention)
Aspirin is a hot topic and has been on my to do list for blogging. Presently, we face the challenge of balancing bleeding risk with primary prevention (2). Future studies, within one decade, should be able to provide reasonable evidence on its risk-benefit ratio. If gastro-intestinal harm and bleeding can be uncoupled from chemoprevention, it might be possible to use Aspirin for broad primary prevention.

Olive oil (chemoprevention, CVD protection)
Recent evidence shows that olive oil is cardioprotective. Only weak evidence links olive oil (or fatty acid saturation) with aging and more studies on this topic are needed. Since olive oil is very resistant to peroxidation, a link to aging is at least plausible, but I am not going to delve into the preliminary data.

II. Mid Term Horizon or more speculative

Translation regulation, nutrient, growth and proliferation sensing

I predict that KO mice and active-site inhibitors will quickly validate several of these downstream and upstream of mTOR. S6K, 4E-BP, ATF4, GCN2 and 4, AMPK, Sirtuins (NAD/NADH ratio??), lipid sensing Lifespan extension through reduced Myc signalling was just recently validated in mice (8), for example. Any reasonably safe inhibitors could be tested in humans, but that is still far away (exception: Metformin, see below).

Selective protein/amino acid restriction, e.g. methionine restriction; other macronutrients
This field will definitely mature, but I do not see much clinical application. Severe restriction is impractical and, again, we will need "mimetics" to treat any larger groups. Modest restriction may realize modest benefits, though.

GH/IGF-1 modulation
Similarly to CR, GH/IGF1 signalling and its link to aging is also controversial. For instance, we do not know how important IGF-1 downstream of GH really is, but I expect that this question will be answered soon. From there, we will need safe drugs to interfere with the GH/IGF1 pathway. Out of the approved drugs the "GH receptor antagonist pegvisomant" is most attractive (6).

Neuropeptide Y signalling
This could be the major upstream pathway responsible for the effects of CR.

Metformin
There is presently little data to suggest that metformin is beneficial to metabolically healthy mice or humans. I foresee minor benefits at best.

Stress resistance, Nrf2 signalling, antioxidants
It is still unclear if Nrf2 is necessary for lifespan extension in general. It does not appear to be required for CR, but it does mediate chemoprevention. I expect the data to become much clearer in the coming decade. But from there? Perhaps, some selective antioxidants will be successful in the end (c.f. mitochondrially targeted catalase).

Autophagy
I am not exactly sure what is holding back the field. However, there are 2 promising interventional studies in mice, or perhaps, I should say only two. ATG5 overexpression (7a) in somewhat short-lived strain and hepatic rejuvenation by the Cuervo lab (7b). Unfortunately, Dr. Cuervo has never responded to my inquiries about extending and reproducing her work.

Advanced Glycation Endproducts
Again, I am not exactly sure what is holding back the field. Since the failure of Alagebrium (around 2013) and some promising studies by Vlassara (around 2007, ref. 9) there has been a dearth of relevant proof of principle studies. I have not kept up with the field, but it seems to have shifted towards diabetes and mechanistic understanding. All in all, I do believe the field may deliver some breakthroughs, but it will take time. Meanwhile reduction of dietary AGEs may provide modest benefits (we don't really know).

Thymic rejuvenation
I cannot comment with confidence on this one, but the data feels quite advanced. There is no human data, however, and I don't think there's any small drug on the horizon that could be used any time soon.

Vitamins and supplements (primary prevention)
Large trials with vitamin D are ongoing (e.g. VITAL study), but I am a skeptical.

Other buzzwords/not my expertise/too early to tell
Inflammation, adipokines, hormesis, mitochondrial aging, sirtuins, NAD/NADH, stem cells, regenerative medicine, telomeres, extracellular matrix, hexosamin pathway.
Brainstorming for future articles (edited on Nov, 2015):
Dietary: coffee, alcohol/red wine, intermittent fasting, phosphate
Supplements: creatine
Combination approaches

References

1. Found on: http://pipeline.corante.com/archives/2015/05/20/a_young_blood_controversy.php
Paper:
Egerman, M. A., Cadena, S. M., Gilbert, J. A., Meyer, A., Nelson, H. N., Swalley, S. E., ... & Glass, D. J. (2015). GDF11 Increases with Age and Inhibits Skeletal Muscle Regeneration. Cell Metabolism.

2. Battistoni, A., Mastromarino, V., Volpe, M., 2015. Reducing Cardiovascular and Cancer Risk: How to Address Global Primary Prevention in Clinical Practice. Clin Cardiol. doi:10.1002/clc.22394

3. F1000Res. 2014 Sep 12;3:219. doi: 10.12688/f1000research.5212.1. eCollection 2014.
Aging and energetics' 'Top 40' future research opportunities 2010-2013.
Allison DB1, Antoine LH2, Ballinger SW3, Bamman MM4, Biga P5, Darley-Usmar VM6, Fisher G7, Gohlke JM8, Halade GV9, Hartman JL10, Hunter GR7, Messina JL11, Nagy TR12, Plaisance EP7, Powell ML5, Roth KA5, Sandel MW13, Schwartz TS14, Smith DL15, Sweatt JD16, Tollefsbol TO5, Watts SA5, Yang Y17, Zhang J18, Austad SN19.

4. Some highlights of research on aging with invertebrates, 2010.
Partridge L.
Aging Cell. 2011 Feb;10(1):5-9. doi: 10.1111/j.1474-9726.2010.00649.x. Epub 2010 Dec 7. Review.

5.
Impact papers on aging in 2009.
Blagosklonny MV, Campisi J, Sinclair DA, Bartke A, Blasco MA, Bonner WM, Bohr VA, Brosh RM Jr, Brunet A, Depinho RA, Donehower LA, Finch CE, Finkel T, Gorospe M, Gudkov AV, Hall MN, Hekimi S, Helfand SL, Karlseder J, Kenyon C, Kroemer G, Longo V, Nussenzweig A, Osiewacz HD, Peeper DS, Rando TA, Rudolph KL, Sassone-Corsi P, Serrano M, Sharpless NE, Skulachev VP, Tilly JL, Tower J, Verdin E, Vijg J.
Aging (Albany NY). 2010 Mar;2(3):111-21. Epub 2010 Mar 23. Review.

6. Aging Cell. 2015 Apr 22. doi: 10.1111/acel.12338. [Epub ahead of print]
Interventions to Slow Aging in Humans: Are We Ready?
Longo VD1, Antebi A, Bartke A, Barzilai N, Brown-Borg HM, Caruso C, Curiel TJ, de Cabo R, Franceschi C, Gems D, Ingram DK, Johnson TE, Kennedy BK, Kenyon C, Klein S, Kopchick JJ, Lepperdinger G, Madeo F, Mirisola MG, Mitchell JR, Passarino G, Rudolph KL, Sedivy JM, Shadel GS, Sinclair DA, Spindler SR, Suh Y, Vijg J, Vinciguerra M, Fontana L.

7a.Nat Commun. 2013 Aug 13;4:2300. doi: 10.1038/ncomms3300.
Overexpression of Atg5 in mice activates autophagy and extends lifespan.
Pyo JO, Yoo SM, Ahn HH, Nah J, Hong SH, Kam TI, Jung S, Jung YK.


7b. Zhang C, Cuervo AM. Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function. Nat. Med. 2008;14:959–965.

8. Reduced expression of MYC increases longevity and enhances healthspan.
Hofmann JW, Zhao X, De Cecco M, Peterson AL, Pagliaroli L, Manivannan J, Hubbard GB, Ikeno Y, Zhang Y, Feng B, Li X, Serre T, Qi W, Van Remmen H, Miller RA, Bath KG, de Cabo R, Xu H, Neretti N, Sedivy JM.
Cell. 2015 Jan 29;160(3):477-88. doi: 10.1016/j.cell.2014.12.016. Epub 2015 Jan 22.

9. Cai W, … Vlasara H. Oral glycotoxins determine the effects of calorie restriction on oxidant stress, age-related diseases, and lifespan. Am J Pathol. 2008;173:327-336.
http://ajp.amjpathol.org/cgi/content/full/173/2/327

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