Unlike the majority of the synthesized proteins, long-lived proteins persist in the body for years.
The majority of cellular proteins are rapidly degraded and replaced with newly synthesized copies, minimizing accumulation of potentially toxic damage and ensuring a functional proteome throughout a cell’s lifetime. Several studies have measured global protein turnover rates in yeast and mammals and reported an average protein half-life of 1.5 hr to 1–2 days, respectively.
In certain tissues, however, a handful of proteins have been shown to persist for months or even years. The persistence of these proteins is remarkable as, in contrast to DNA, another long-lived molecule, dedicated repair mechanisms have not been established for proteins with long lifespans.
Understanding the aging process
The identiﬁcation and characterization of long-lived proteins has potential implications for age-related defects in tissue homeostasis. For both crystallin and collagen, it was shown that their lifespans resulted in accumulation of damage that manifested as cataract eye lenses and cartilage stiffening, respectively.
In summary, proteins with exceptional lifespans might be sources of vulnerability in the mammalian proteome, and their identiﬁcation is thus critical for our understanding of the aging process in tissues.
A study recently published in Cell sought to conduct a systematic analysis of the long-lived proteome for an entire organism during aging. To achieve this, the team employed a unique pulse-chase labeling time course of rats.
In brief, female rats were fed a diet containing exclusively the 15N isotope just after weaning. Progeny born from these females were efficiently labeled with the 15N isotope and were continued on this diet for 6 weeks after birth (pulse). After this period, the pulse-labeled animals were switched to a normal 14N diet (chase). Rats were sacriﬁced at 0, 4, 6, 9, and 12 months postchase, and all tissues were harvested and stored for analysis.
Persistence of 15N peptides in pulse-chased animals indicates a lack of degradation of their corresponding proteins, and these proteins were define as long-lived.
The team compared the proteome of the adult brain, an organ with limited capacity for regeneration and with very longlived cells, to that of the liver, which in rodents has been shown to renew its constituent cells within
As expected, analysis of 15N spectral counts across the different fractions revealed a 10-fold greater 15N content in the brain over the liver.
A common phenomenon
The more surprising observation is that long-lived proteins are much more common than previously appreciated. Also, the long-lived proteome is composed of functionally diverse proteins that regulate a myriad of cellular functions.
Although the existence of a long-lived proteome is now evident, the prevailing question still remains: Why would the cell employ proteins with limited turnover if their persistence places them at increased risk for damage accumulation? A common, but not exclusive, characteristic of the long-lived proteins identified in this study is their involvement in large and stable cellular structures.
However, some long-lived proteins lacked association with any apparent stable structures and include several enzymes. How or why seemingly soluble proteins persist through aging is puzzling, particularly for proteins with enzymatic activity. How these unique long-lived proteins evade turnover, whether they are part of large protein assemblies that have to be maintained over time, and if they exhibit any age-dependent loss of function will be of great interest for future studies.
Toyama BH, Savas JN, Park SK, Harris MS, Ingolia NT, Yates JR 3rd, & Hetzer MW (2013). Identification of long-lived proteins reveals exceptional stability of essential cellular structures. Cell, 154 (5), 971-82 PMID: 23993091