Cells are “factories” and proteins are “machines”
In previous parts, we mainly discussed the mishaps that accumulate on the genome that cause aging. In this article, we will move our focus to protein.
When talking about proteins, the first thing that comes to people’s mind might be food. Indeed, protein is one of the essential nutrients, but it is a lot more than that. In the living organism, the proteins carry out most of the “life reactions.” If we consider a cell as a factory, then DNA is the “blueprint” that is used to produce the RNA and then protein. Moreover, protein is the “machine” that does the “actual jobs” to sustain the cell’s survival.
In fact, most of the phenotypes we observe are mediated by proteins. Muscle contraction is mediated by myosin and actin; the neuronal firing are mediated by membrane proteins that change the charge of the neuron; even the cellular structures are sustained by the structural protein called tubulin and actin.
As machines, proteins need to be maintained
The machines in a factory need to be regularly maintained, broken machines need to be repaired, and old machines need to be removed to make space. Also, everything needs to be organized to make sure all the machines work properly. Similarly, all cells take advantage of an array of quality control mechanisms to preserve the stability and functionality of their proteomes (the collection of all proteins).
Proteostasis involves mechanisms for stabilizing correctly folded proteins and mechanisms for the degradation of proteins by the proteasome or the lysosome. Moreover, regulators of age-related proteotoxicity act through an alternative pathway distinct from molecular chaperones and proteases (van Ham et al., 2010).
All of these systems function in a coordinated fashion to restore the structure of misfolded polypeptides or to remove and degrade them completely, thus preventing the accumulation of damaged components and assuring the continuous renewal of intracellular proteins (Lopez-Otin et al., 2013).
Proteostasis is gradually lost during aging
Many studies have demonstrated that proteostasis is altered with aging. Additionally, chronic expression of unfolded, misfolded, or aggregated proteins contributes to the development of some age-related diseases, such as Alzheimer’s disease, Parkinson’s disease, and cataracts (Powers et al., 2009). Here, we will focus on two main mechanisms of protein maintainance: chaperone-mediated protein folding, which ensures the “machines” are assembled correctly; and proteolytic system, which removes the old, damaged “machine.”
Chaperone-mediated protein folding and aging
The stress-induced synthesis of chaperones is impaired in aging, and many studies show that it is causal to early death. For example, the transgenic worms and files that are over-expressing chaperones have a longer lifespan. Also, in mutant mice with deficient co-chaperone, aging is accelerated (Min et al., 2008).
Moreover, activation of the master regulator of the heat-shock response, the transcription factor HSF-1 increases longevity and thermotolerance in nematodes (Chiang et al., 2012; Hsu et al., 2003), while amyloid-binding components can maintain proteostasis during aging and extend lifespan (Alavez et al., 2011). In mammalian cells, deacetylation of HSF-1 by SIRT1 potentiates the transactivation of heat-shock genes such as Hsp70, whereas downregulation of SIRT1 attenuates the heat-shock response (Westerheide et al., 2009).
Proteolytic systems declines during aging
There are two principal proteolytic systems implicated in protein quality control: the autophagy-lysosomal system and the ubiquitin-proteasome system. Both systems decline with aging.
Regarding autophagy, transgenic mice with an extra copy of the chaperone-mediated autophagy receptor do not experience an aging-associated decline in autophagic activity and preserve improved hepatic function with aging (Zhang and Cuervo, 2008). Interventions using chemical inducers of macro-autophagy have spurred extraordinary interest after the discovery that constant or intermittent administration of the mTOR inhibitor rapamycin can increase the lifespan of mice (Blagosklonny, 2011; Harrison et al., 2009).
Notably, rapamycin delays multiple aspects of aging in mice. The lifespan-extending effect of rapamycin is strictly dependent on the induction of autophagy in yeast, nematodes, and flies. Spermidine, another macroautophagy inducer that, in contrast to rapamycin, has no immunosuppressive side effects, also promotes longevity in yeast, flies, and worms via the induction of autophagy (Eisenberg et al., 2009). Similarly, nutrient supplementation with spermidine increases longevity in mice.
NAD+ and proteostasis
The interest in NAD+, in the context of proteostasis, emerged with the discoveries that sirtuins can modulate proteostasis, particularly the autophagy degradation pathway and aging.
Analysis of sequence variants within the SIRT1 gene promoter regions in Parkinson’s disease patients revealed the existence of three sequence variants, suggesting that polymorphisms may alter the transcription factor sites of SIRT1 gene promoter resulting in decreased SIRT1 levels and increased PD risk. This change on Sirt1 levels could underlie alterations on lysosome degradation processes, which is also supported by observations in the brain of Alzheimer’s disease patients, where a deficiency in SIRT1 leads to hyperacetylation of the phosphorylated tau, resulting in impaired tau degradation by the proteasome and by autophagy.
Overexpression of SIRT1 in animal and cell PD models was shown to suppress protein aggregates’ formation by the activation of HSF1, which affects transcription of molecular chaperones. The promoted effects of SIRT1 are believed to be at least partially depended on its ability to induce autophagy, as shown in human cells in vitro and in C. elegans in vivo.
NAD+ boosters restore proteostasis
There are several studies showing that administration of NAD+ boosters can restore the age-related Loss of proteostasis. A recent study suggests that the replenishment of intracellular NAD+ by providing NR reduces neurotoxic protein aggregates of mitochondria and restores the proteostasis in the brain of SOD1-mutated mice (Zhou et al., 2020).
In addition, nicotinamide mononucleotide (NMN) administration rescues aged-impaired proteostasis in kidneys and significantly increased the number of peroxisomes in aged mouse kidneys, indicating that NMN enhanced peroxisome biogenesis, and suggesting that it might be beneficial to reduce kidney injuries (Yi et al., 2020).