We are pretty sure that insufficient protein catabolism plays a role in aging (1-7). Important age-related pathologies include (extracellular) amyloidoses, inside and outside the brain, like those in Alzheimer's disease or less widely known in transthyretin amyloidosis. Intracellular aggregates include α-synuclein (AS) in the case of Parkinson's disease. In addition, intra-lysosomal protein-containing aggregates accumulate with aging, e.g. lipofuscin, or "A2E" in the retina. The interested reader is referred to reviews by Terman and Brunk (4), Rubinsztein (2), Cuervo (7) as well as the SENS-Foundation blog.
As an example of the proteostasis-aging link, enhanced autophagy is generally beneficial and associated with extended lifespan or rejuvenation (1, 2). Unfortunately, barring a few exceptional studies with specific interventions (1), most data is indirect ("rapamycin extends lifespan and also increases autophagy"), confounded (offtarget effects, generally) or of little translational relevance (lifespan extension in invertebrates).
A credible in vivo test of the "protein homeostasis hypothesis" would require that multiple inducers of autophagy extend lifespan in long-lived mice. The same goes for inducers of the proteasome, unfolded protein response, or chaperone mediated autophagy (CMA). So far, rapamycin, and perhaps calorie restriction, are the only examples of autophagy inducing interventions shown to extend lifespan in healthy rodents. I might be missing some, but there are only few in any case.
Now, a recent study (3) has made me question the importance of the proteasome compared to CMA and general autophagy. Since catabolic pathways are interlinked, evidence against the "proteasome hypothesis" weakens the "autophagy/CMA hypothesis" and is worth investigating, no matter your preferred hypothesis.
Is proteasomal acitivity related to aging?
A quick glance at the literature (3, 4, 5, 6, 7 and so on) suggests to me that the 2011 paper by Salway et al. (3) is the most comprehensive on this topic (3). It's a comparative study of aging, which is, in principle, a very powerful tool (8).
Salway et al. 2011 studied 15 species and their 20/26S proteasomal activity in tissue homogenates. These authors found no relevant differences.
Interestingly, some current reviews disagree with their conclusion (5) without actually citing this important paper and bringing forward arguments. I am no expert, but I await refutation and actual methodological criticism. For now, the work by Salway et al. seems solid and demands an explanation.
Other strands of evidence also argue against the importance of the proteasome. Just to give a few examples, Methylene Blue is cited as an in vivo inducer of the proteasome (5) but fails to deliver relevant lifespan extension. IGF-1 is an inducer yet epitomizes pro-aging:
"Transgenic mice that overproduce IGF-1 exhibit reduced levels of oxidized proteins and high CT-L [chymotrypsin-like] activity of the 20 S and 26 S proteasomes in their frontal cortex. The same results have also been observed after stimulation with IGF-1 in cell cultures..."
Finally, Nrf2 signalling is thought to upregulate the proteasome, but the long-lived Snell dwarf mouse (3), which shows elevated Nrf2-signalling, has normal proteasomal activity. All that is indirect evidence, but we have to take it seriously.
How can it be that protein homeostasis is important nonetheless?
Barja et al. speculate that the generation of damage is reduced in long-lived species, because other mechanisms are too inefficient. Apparently, generation of damage is so much lower that antioxidant defenses are decreased in long-lived species, according to some studies. However, the latter idea seems contradictory, as in its simplest form it would imply that antioxidant defenses could actually slow aging. Why? Barja suggests that reduced generation of damage and increaseed antioxidant defenses are interchangeble and one can substitute for the other; that's what this indirect relationship implies.
There's a problem with this line of thought. The notion that antioxidant defenses extend lifespan has been refuted experimentally and there's no reason why organisms shouldn't increase both.
Of course, this is a simplification on my part as A. antioxidative defenses may be useful as part of a broader stress resistance phenotype and B. some sort of "disposable soma" theory can help to explain these differences (allocation of scarce resources), C. the antioxidant data might be artifactual.
Either way, most people believe that damage repair is also important. In this case, perhaps, the proteasome is not generally the "bottleneck" for protein degredation. It seems plausible to believe that, for instance, disaggregating proteins might be more important. Or wholesale destruction in autolysosomes. Or the prevention of irreversible aggregation (9).
It seems unlikely that insoluble aggregates could be degraded: "One limitation for the proteasome to clear protein aggregates is that the large size and proteolytic stability of misfolded aggregates pose difficulties for them to enter into the proteasome chamber that has a pore size of 13 angstroms." (6)
Maybe lamp2a/chaperone mediated autophagy is more relevant to aging, which would be consistent with the data by Cuervo (1).
What we need are lifespan studies in long-lived rodents. In particular, a test of Cuervo's genetic lamp2a upregulation (2) and different independent, inducers of auophagy.
1. Nat Med. 2008 Sep;14(9):959-65. doi: 10.1038/nm.1851.
Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function.
Zhang C1, Cuervo AM.
2. Cell. 2011 Sep 2;146(5):682-95. doi: 10.1016/j.cell.2011.07.030.
Autophagy and aging.
Rubinsztein DC1, Mariño G, Kroemer G.
3. Age (Dordr). 2011 Mar;33(1):33-47. doi: 10.1007/s11357-010-9157-5. Epub 2010 Jun 22. Enhanced protein repair and recycling are not correlated with longevity in 15 vertebrate endotherm species. Salway KD1, Page MM, Faure PA, Burness G, Stuart JA.
4. Antioxid Redox Signal. 2010 Apr;12(4):503-35. doi: 10.1089/ars.2009.2598. Mitochondrial turnover and aging of long-lived postmitotic cells: the mitochondrial-lysosomal axis theory of aging.Terman A1, Kurz T, Navratil M, Arriaga EA, Brunk UT.
5. Free Radic Biol Med. 2014 Mar 26. pii: S0891-5849(14)00148-8. doi: 10.1016/j.freeradbiomed.2014.03.031. [Epub ahead of print]
Proteasome Activation Delays Aging in Vitro and in Vivo.
Chondrogianni N1, Sakellari M2, Lefaki M1, Papaevgeniou N1, Gonos ES2.
6. Int J Cell Biol. 2013;2013:638083. Epub 2013 Nov 17.
Role of Protein Misfolding and Proteostasis Deficiency in Protein Misfolding Diseases and Aging.
Cuanalo-Contreras K1, Mukherjee A2, Soto C2.
7. Cell Res. 2014 Jan;24(1):92-104. doi: 10.1038/cr.2013.153. Epub 2013 Nov 26.
Chaperone-mediated autophagy: roles in disease and aging.
Cuervo AM1, Wong E2.
8. Integr Comp Biol. 2010 Nov;50(5):783-92. doi: 10.1093/icb/icq131. Epub 2010 Sep 16.
Cats, "rats," and bats: the comparative biology of aging in the 21st century.
9. Mech Ageing Dev. 2011 Jun-Jul;132(6-7):287-97. doi: 10.1016/j.mad.2011.06.002. Epub 2011 Jun 15.
Higher levels of heat shock proteins in longer-lived mammals and birds.
Salway KD1, Gallagher EJ, Page MM, Stuart JA.