The link between protein synthesis and mitochondrial degradation: Towards a unified mechanism of aging

The fidelity of protein synthesis is necessary for a properly functioning organism. In an aged animal, the overall rates of protein synthesis and degradation/recycling decline with age. Not only does this decrease the number of structural and enzymatic proteins available, but it increases the half life of proteins, perhaps allowing more time for these proteins to become oxidatively damaged.

Protein synthesis is also linked to nutrient availability through the TOR signaling pathway, implicating protein synthesis in the mechanism of life extension by calorie restriction (CR). CR counteracts the decline in protein turnover seen with age. Inhibiting protein synthesis also increases lifespan in C. elegans.

Wang et al examined the link between the rate of protein synthesis and mitochondrial degeneration. Working in yeast, they introduced a mutation into adenine nucleotide translocase (aac2A128P), a protein located on the mitochondrial membrane. This mutation mimics the human disease progressive external ophthalmoplegia (PEO). The authors speculate that aac2A128P might upset the availability of nucleotides, which in turn could cause deletions of mtDNA, a hallmark of PEO. In addition, they show that the introduction of aac2A128P causes a decrease in membrane potential, which has already been shown to play a key role in aged mitochondria. aac2A128P mutants also have a decreased replicative lifespan.

The authors next tested whether any known lifespan-extending mutations can suppress the mitochondrial dysfunction induced by the aac2A128P mutation. Three of these mutations were particularly robust in reversing the aac2A128P mutation. sch9Δ, rpl6BΔ and rei1Δ on a aac2A128P background were able to form viable colonies at almost wild type levels. SCH9 is involved in nutrient sensing; RPL6B is a protein that makes up the ribosome; and REI1 is involved in ribosome processing. Overexpression of the well-known yeast sirtuin SIR2 did not have any effect on replicative lifespan in the aac2A128P mutant.

sch9Δ, rpl6BΔ and rei1Δ mutants, even with the aac2A128P mutation, outlived their wild type counterparts. The lethal aac2A128P/phb1Δ double mutant was still viable with these three life-extending mutations. phb1Δ mutants have reduced mitochondrial membrane potentials and are susceptible to ethidium bromide. sch9Δ, rpl6BΔ and rei1Δ mutants on a phb1Δ background were resistant to ethidium bromide. CR had similar effects as these three lifespan-extending mutants, but other long-lived mutants, like tor1Δ, were only able to suppress the aac2A128P – and not the aac2A128P/phb1Δ double mutant – defect in mitochondrial membrane potential.

Might mitochondrial membrane potential be linked to protein synthesis? The researchers found that all of the lifespan-extending mutations examined had reduced total protein synthesis. sch9Δ, rpl6BΔ and rei1Δ mutants had some of the largest decreases. According to the authors, lower rates of protein translation will reduce stress from unassembled protein complexes. “Reduction of cytosolic protein synthesis may lower the overall loading of proteins onto the mitochondrial inner membrane and promote mitochondrial membrane potential maintenance.”

To examine the link between mitochondrial membrane potential and protein synthesis, the authors looked at the yme1Δ mutant. YME1 encodes a protease important for protein turnover, so, according to the authors, the altered mitochondrial membrane potential of the aac2A128P mutant will worsen with decreased protein turnover. sch9Δ, rpl6BΔ and rei1Δ mutants were able to suppress the lethal aac2A128P/yme1Δ double mutant.

This paper links two aging-associated deficiencies: mitochondrial defects and decreases in protein synthesis. These connections are becoming more and more common in the aging field. But why did some life-extending mutations cause reversions in the aac2A128P mutant while others didn’t? How many paths are there to extended longevity?

The data above presents another conundrum. Protein synthesis declines with age, yet decreasing protein synthesis extends lifespan. What’s going on here? My guess is that decreased protein synthesis when you’re young in addition to inhibiting the decline in protein translation as you get older will delay the aging process.



  1. […] The link between protein synthesis and mitochondrial degradation: Towards a unified mechanism of agi… And one for the biomedically-inclined molecular biologist. […]

  2. Aging Seen Without The Emperor’s New Clothes
    ( recapitulation )

    More and more research works related to old age are published in scientific periodicals.
    About time to realize that the aging of genes contributes to organisms aging.

    A. Aging, lifetime and age

    Aging = to become old, show the effects or the characteristics of increasing age, the increasing liferime. The effects and characteristics of not only the totality of the system, but also of each and every component, and of components of the components of the system. The system is the totality of the components.

    lifetime = the duration of the existence of a living being, an organism, or an inanimate thing, a material, star or subatomic particle.

    age = the length of an existence extending from its beginning to any given time.

    B. More and more research works related to old age are published in scientific periodicals

    The lengthening list of work-accounts comprises a wide array of subjects apparently related to old age, including:

    – A variety of constitutional impairments,
    – a variety of impaired biological processes,
    – a variety of impaired genetic materials and expressions,
    – a great variety of suggested things to consume or do or avoid for alleviating the symptoms,
    – and a great variety of anti-aging suggestions.

    C. Some examples of statements:

    – A little stress may keep cells youthful.
    – Intestinal stem cells, that replenish the lining, go awry in elderly flies, similar to what
    happens in certain human stem cell populations.
    – Yeast, worms and people may age by similar mechanisms.
    – Nearly all organisms experience aging.
    – In aging muscles and neurological problems, energy greedy organs, there are mitochondria
    – Age-related growing ‘leakiness’ in cell nucleus membrane may contribute to aging and even to
    diseases such as Parkinson’s and Alzheimer’s.
    – Age-Related Hearing Impairment, presbycusis, is a complex elderlies disease caused by
    overexpression of glutamate due to interaction between environmental and genetic factors.

    D. Right they are: “Nearly all organisms experience aging”. But why “nearly”?

    Why don’t “scientists” accept the obvious fact that genes are organisms and “experience aging”, too?

    Not only yeast, worms and people. Also genes and the interdependent-genes-communes, genomes. Theye are both organisms. They are alive. It is their “lifehood” that makes us and all life forms “alive”.

    By plain common sense – my favorite scientific approach – they should also be “experiencing aging”…

    E. The aging of genes contributes to organisms aging

    Since a genome is a cooperative commune of interdependent genes, many of its member genes “modulate its aging” to various extents at various time-rates depending on circumstances and environment and on their individual composition and functioning history. Various things happen to them or affect them and impair their functionalities.

    In my plain commonsensical mind “interaction between environmental and genetic factors” is a description of organism’s “aging”. And in my boy’s-like view of the emperor’s new clothes organism’s aging comprises aging of its genes-genome, and genes and genomes age as we age, and we age also as a result of the aging of our genes and genomes…

    F. Finally, re “Theories about human cellular aging supported by new research”

    “Research presented at American Society for Cell Biology conference:
    Aging yeast cells accumulate damage over time, but they do so by following a pattern laid down earlier in their life by diet as well as the genes that control metabolism and the dynamics of cell structures such as mitochondria, the power plants of cells.”

    Cellular Aging? What is Cellular Aging?

    Complexly instrumented future spacestations accumulate damage over time, and their residents, too, age and accumulate damage over time. Yes, the functionality of the stations’ residents and of their intruments and equipment is impaired with age. Wonder why?

    The reason for the impairment with age of the highly active instrumented-equipped stations and of their resident crew is that they “follow a pattern laid down earlier in their life by diet as well as by the residents who control metabolism and the dynamics of the stations’ structures such as mitochondria, their power plants.”

    G. Enough. Cells just house organisms. The resident genes-genomes are THE organisms.

    About time that “scientists” refresh conceptions and comprehensions and attitudes and research plannings and peer-reviewings. Let their science evolve…

    Dov Henis
    (Comments From The 22nd Century)–?cq=1

    EVOLUTION Beyond Darwin 200

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