Fight Aging! Newsletter, February 27th 2023

Endothelial progenitor cells (EPCs), obtained from peripheral blood and identified as CD34 antigen-positive (CD34+) mononuclear cells, were marrow-derived stem cells and can differentiate into endothelial cells to promote neovascularisation in response to ischemic injury. Cell therapy using EPCs has been shown beneficial in ischaemia-related cardiovascular diseases (CVD) and emerged as useful substrates for neovascularization. However, some limitations make their clinical application difficult, such as heterogeneity in progenitor cell types, lack of standardization of specific surface markers and reduced number during ageing. Nonetheless, the angiogenic potential of EPCs has been an important target in regenerative medicine.

Numerous studies indicated that microRNA (miR or miRNA) is involved in post-transcriptional regulation of gene expression concerning diverse biological functions, including ageing and angiogenesis. A previous report showed that angiogenesis and tissue repair were regulated by miRNA-135a-3p via targeting p38 signalling in endothelial cells, revealing a link among miRNA, angiogenesis, and endothelial cells. In addition, increased miRNA-183-5p with age was involved in stem cell senescence. Furthermore, several studies have also addressed the regulation of miRNA during culture-induced senescence of vascular cells or in tissues.

These findings suggested that senescence and miRNAs may play an integrated role in modulating the pathologic processes of human CVD via the regulation of progenitor cell activity. We, therefore, in the present study explored the roles of hsa-microRNA (miR)-409-3p in senescence and signalling mechanism of human endothelial progenitor cells (EPCs). Hsa-miR-409-3p was found upregulated in senescent EPCs. Overexpression of miRNA mimics in young EPCs inhibited angiogenesis. In senescent EPCs, compared to young EPCs, protein phosphatase 2A (PP2A) was downregulated, with activation of p38/JNK by phosphorylation. Young EPCs treated with PP2A siRNA caused inhibited angiogenesis with activation of p38/JNK, similar to findings in senescent EPCs.

Inhibited angiogenesis of young EPCs after miRNA-409-3p mimics treatment was reversed by the p38 inhibitor. The effect of hsa-miR-409-3p on PP2A signalling was attenuated by exogenous VEGF. Analysis of human peripheral blood mononuclear cells (PBMCs) obtained from healthy people revealed hsa-miR-409-3p expression was higher in those older than 65 years, compared to those younger than 30 years, regardless of gender. In summary, hsa-miR-409-3p was upregulated in senescent EPCs and acted as a negative modulator of angiogenesis by regulating PP2A/p38 signalling.

The molecular biology of cellular senescence has opened the possibility of exploiting the differential vulnerabilities of senescent cells (SCs) compared with healthy cells for the development of a new class of longevity therapeutics against aging and age-related disorders. However, the significant heterogeneity among SCs based on cell type of origin or senescence induction method suggests the need to develop senolytics that either have a broader therapeutic efficacy or that can target recalcitrant SCs.

In this context, paracrine senescence (PS) is the least understood type of senescence. Even though there have been previous efforts to characterize PSs, the fact that only a subset of cells exposed to the senescence-associated secretory phenotype (SASP) factors become senescent means that previous experimental protocols were compromised, with mixed cell populations dominated by non-senescent cells labeled as PSs. We were able to circumvent this major methodological issue by isolating and enriching PSs using the previously characterized SC surface marker DPP4.

We discovered that DPP4+ paracrine SCs (PSDPP4+) engage prosurvival pathways that are distinct from those on which DPP4+ primary SCs (SDPP4+) rely and are also relatively resistant to killing by senolytic drugs previously identified to be effective against primary SCs. Given that SCs accumulate ferrous iron (Fe(II), also known as labile iron), we sought to test a Fe(II)-targeting strategy in which Fenton reaction of a prodrug was coupled to release of drug payload. Others previously showed that the tumor-activated prodrug TRX-CBI (comprising a trioxolane-based [TRX] sensor of Fe(II) conjugated to a cytotoxic cyclopropylbenzindoline [CBI] payload) demonstrated selective toxicity in Fe(II)-rich cancer cells.

Here, we used a form of TRX-CBI to target cytotoxic CBI to SCs. We demonstrated that treatment with TRX-CBI triggers significant senolysis of both PSDPP4+ and SDPP4+, with negligible cytotoxicity toward non-senescent cells. Based on our results, we propose Fe(II)-based targeting of SCs with ferroptosis inducers or iron-activated drug conjugates as broad-spectrum senolytic agents.

Despite the economic challenges of 2022, the emerging longevity biotech industry made impressive progress on several fronts, including positive results in clinical trials of senolytics and mitochondrial replacement therapies. Unity Biotechnology, backed by billionaires Jeff Bezos and Peter Thiel, reported positive results from a multicenter randomized clinical trial of a new senolytic drug to treat diabetic macular edema, a common cause of blindness in diabetic patients. Several companies, including Deciduous Therapeutics, Oisin Biotechnologies, and Cleara Biotech, are developing senolytic therapies to treat debilitating chronic conditions such as pulmonary fibrosis, diabetes, and cancer.

Mitochondrial replacement to restore cellular energy production is expected to be highly impactful for age reversal. Minovia, an Israeli biotech company, demonstrated the feasibility of transplanting mitochondria into humans. Although Minovia is treating an illness, their achievement suggests that a similar treatment could be used to enhance healthspan. In Minovia's clinical trial, children with single large-scale mitochondrial DNA deletion syndromes, a class of severe congenital mitochondrial diseases, received healthy mitochondria from their mothers. The benefits of the therapy were still evident one year after the transplant. Multiple startups are working on treatments to restore or replace aging mitochondria, including Mitrix Bio, Cellvie, Stealth BioTherapeutics, and Yuva Biosciences.

If proven feasible, cellular reprogramming could restore cell health and resilience, and treat diseases and disabilities caused by aging. 2021 and 2022 were the setup years for reprogramming with billions in funding and several ventures started. Ventures working on reprogramming include Altos Labs, NewLimit, Calico, Life Biosciences, Rejuvenate Bio, and Turn Biotechnologies. Altos Labs scientist Dr. Reik developed a method to reprogram cells, reversing their biological age by 30 years. Another Altos Labs scientist, Dr. Izpisua Belmonte, showed that long-term reprogramming was safe and could reverse age-related organ damage in mice. His group also developed an RNA-based therapy to reverse biological age and reduce inflammation in mice.

During the lifetime of an organism, proteins are constantly exposed to stressors that impair their function. Protein homeostasis networks have evolved to monitor and regulate the synthesis, folding, trafficking, and degradation of proteins. The earliest process in the protein life cycle that modulates cellular proteostasis is translation. Changes in levels or mutations in the components of translational machinery have a significant impact on longevity in several animals. For instance, mutation or depletion of ribosomal proteins and translation factors extend lifespan in yeast worms and flies. Similarly, blocking the mTOR (mammalian Target of Rapamycin) system through rapamycin reduces protein synthesis and increases lifespan. While the significance of protein synthesis in the aging process is widely accepted, it is unclear whether errors in protein synthesis or translational fidelity may play a part in aging per se.

Protein synthesis error rates in bacterial systems are estimated to be as high as 1 in 10^3 per amino acid. According to this estimation, up to 15%-20% of the cellular protein pool may contain mistranslation errors. Mistranslated proteins may not have a significant impact on cellular proteostasis at a young age, due in part to the quick turnover and efficient clearance of cellular proteins. However, in the older animal, protein turnover rates, proteasome activity, and autophagy decline, making them more sensitive to error-prone protein translation. Therefore, mistakes in protein translation have the potential to cause a variety of age-related diseases. So far, however, it was unclear whether accurate translation can affect cellular aging and if the rate and extent of mistranslation increase with aging.

Researchers recently proposed a mechanism of aging that is highly dependent on translational accuracy. The authors study ribosomal protein RPS23, a homolog of prokaryotic S12 protein that is conserved in all three domains of life, and implicate it in the maintenance of protein translational accuracy. The ribosomal protein S12 (eukaryotic homolog RPS23) contributes to translation accuracy. A single amino acid alteration in a ribosomal protein present in archaea can improve metazoan translation fidelity and survival. The authors conducted a comprehensive phylogenetic analysis of RPS23 and discovered that a lysine residue at position 60 is evolutionarily conserved, except in hyperthermophilic archaea, where arginine replaces it (RPS23-K60R).

CRISPR gene editing was used to insert a mutation into the Drosophila melanogaster Rps23 gene, which led to the substitution of the lysine 60 with an arginine residue. The translational accuracy of mutant and wild-type flies was determined with a reporter construct that contained a renilla luciferase gene followed by a firefly luciferase gene separated by an in-frame linker sequence containing a stop codon. Inclusion of a stop codon produces firefly only if a read-through error had occurred, and thus served as a measure of translational accuracy. It was discovered that the K60R mutation in the RPS23 protein decreased the frequency of mistakes made during protein synthesis, thereby leading to a reduction in firefly luciferase production in the mutants. Specifically, the stop-codon read-through increased considerably with aging in the control flies, but not in the RPS23-K60R mutant. Similar results were obtained in Caenorhabditis elegans and Schizosaccharomyces pombe (yeast), where the expression of the RPS23-K60R protein also reduced stop-codon read-through.

Given that the variant (RPS23 K60R) was initially discovered in hyperthermophilic archaea, the authors contended that the protein should provide an evolutionarily conserved mechanism of heat tolerance. Indeed, flies, worms, and yeast expressing RPS23-K60R protein were able to grow and survive at temperatures above the optimum. Finally, the physiological benefit of this mutation was demonstrated by an increase in healthy lifespan. The authors demonstrate that when the mutation was introduced, it improved lifespan by 9%-23% in all three model organisms. Additionally, the authors extend their findings by noting that treatments that prolong lifespan (such as rapamycin) do so by enhancing translational fidelity in controls but not in mutant K60R strains. Thus, they concluded that the primary determinant of the aging process was a reduction in translational fidelity.

In this study, we explored the impact of T cell senescence on the renal prognosis and mortality of patients with chronic kidney disease (CKD). We found that decreased recent thymic emigrant (RTE) T cells, which corresponds to decreased thymic output, was associated with CKD progression and high mortality, and an increase in highly differentiated CD28-CD4+ T cells, which increases with age, tended to be associated with CKD progression. Thymic atrophy is a characteristic of an aging immune system and has been implicated in age-related diseases such as infection, malignancy, atherosclerosis, and CKD. However, epidemiologic data are limited in patients with non-dialysis-dependent CKD. To our knowledge, this is the first study to demonstrate the impact of decreased thymic output on renal prognosis and all-cause mortality in patients with non-dialysis-dependent CKD.

An immunological model has been constructed using epidemiological and immunological data to show that an age-related decrease in thymic output is associated with the development of infectious diseases and malignancies. Decreased RTE in renal transplant patients increases all-cause mortality. In dialysis patients, decreased RTE is associated with death caused by infection, and decreased naive T cell count due to thymic atrophy increase all-cause mortality. Furthermore, our results are consistent with previous findings showing that shorter telomeres in peripheral blood leukocytes worsen renal prognosis and mortality, because the decrease in naive T cell counts due to thymic atrophy is compensated by increased T cell division, thereby shortening telomeres.

There are three potential mechanisms by which decreased thymic output contributes to CKD progression and increased mortality. (a) Low thymic output reduces the diversity of TCR repertoire and may reduce the clearance of senescent cells by immune cells. (b) When the number of newly produced naive T cells decreases, homeostatic proliferation maintains the peripheral T cell count. However, homeostatic proliferation increases the percentage of dysfunctional memory-type T cells in mice. These T cells secrete inflammatory chemokines involved in chronic tissue inflammation, delay kidney tissue repair after acute kidney injury, and may be associated with CKD progression. (c) Thymic atrophy may reflect a systemic state of aging. As aging progresses, local and systemic inflammation induced by senescent-associated secretory phenotype (SASP) causes organ damage, which may cause thymic atrophy and decreases kidney function, and increase mortality. Conversely, the presence of CKD decreases thymic output, increasing the susceptibility to further progression of CKD and high mortality.

An important aspect of survival is to assure enough food, water, and oxygen. Here, we describe a recently discovered response that favors survival in times of scarcity, and it is initiated by either ingestion or production of fructose. Unlike glucose, which is a source for immediate energy needs, fructose metabolism results in an orchestrated response to encourage food and water intake, reduce resting metabolism, stimulate fat and glycogen accumulation, and induce insulin resistance as a means to reduce metabolism and preserve glucose supply for the brain. How this survival mechanism affects brain metabolism, which in a resting human amounts to 20% of the overall energy demand, is only beginning to be understood.

Here, we review and extend a previous hypothesis that this survival mechanism has a major role in the development of Alzheimer's disease and may account for many of the early features, including cerebral glucose hypometabolism, mitochondrial dysfunction, and neuroinflammation. We propose that the pathway can be engaged in multiple ways, including diets high in sugar, high glycemic carbohydrates, and salt. In summary, we propose that Alzheimer's disease may be the consequence of a maladaptation to an evolutionary-based survival pathway and what had served to enhance survival acutely becomes injurious when engaged for extensive periods. Although more studies are needed on the role of fructose metabolism and its metabolite, uric acid, in Alzheimer's disease, we suggest that both dietary and pharmacologic trials to reduce fructose exposure or block fructose metabolism should be performed to determine whether there is potential benefit in the prevention, management, or treatment of this disease.

Centenarians exhibit extreme longevity and have been postulated, by some researchers, as a model for healthy aging. The identification of the characteristics of centenarians might be useful to understand the process of human aging. In this retrospective study, we took advantage of demographic, clinical, biological, and functional data of deceased individuals between 2014 and 2020 taken from the Basque Health Service electronic health records data lake. Fifty characteristics derived from demographic, clinical, pharmaceutical, biological, and functional data were studied in the descriptive analysis and compared through differences in means tests. Twenty-seven of them were used to build machine learning models in the predictive analysis and their relevance for classifying centenarians was assessed.

Most centenarians were women and lived in nursing homes. Importantly, they developed fewer diseases, took fewer drugs, and required fewer medical attendances. They also showed better biological profiles, exhibiting lower levels of glucose, hemoglobin, glycosylated hemoglobin, and triglycerides in blood analysis compared with non-centenarians. In addition, machine learning analyses revealed the main characteristics of the profiles associated with centenarians' status as being women, having fewer consultations, having fewer diagnoses of neoplasms, and having lower levels of hemoglobin.

Aging is a set of molecular and cellular processes that affects us all, but what if we could extend our healthy lifespan and live longer, healthier lives? This is the goal of the rapidly growing field of longevity. And after my last post about leaving my CTO job to work on longevity a lot of people have reached out asking what I'm working on actually? What I'm building for longevity? The short answer is... nothing. Yet. The long answer is... well, this post. I believe that anyone can work on anything they put their mind to if they are willing to put in the time and effort to learn the necessary skills. Whether it's research, funding, talent, media, practical longevity, aging therapeutics, or infrastructure, there are numerous opportunities to make a significant impact in this field.

6.96 billion was raised across 96 funding rounds in 2022. This may seem like a lot but it's actually nothing. Remember that Instagram was acquired for 1 billion. So trying to bring more funding to the longevity field is very much needed. Someone needs to help talented people transition into the field. And believe me, we need far, far more people working on longevity. Recruiting and community building are important. The narrative around longevity is changing towards a more strategic conservatism which is proving to have better adoption. But it's far away from reaching a mainstream level. We need more communicators designing and evolving new narratives for different people.

The first drug targeted to extend healthy lifespan by 10-20 years could be developed and commercialized this decade. Aging therapeutics usually means getting the science out of the lab. So most often than not, someone with biology background will try to start or join a startup around their expertise. But what about people who are not coming from academia? The reality is that it may take anything from 6 months to 1 year (maybe even more) of full dedication to gain enough context, map the gaps, understand low hanging fruits, understand which technologies are the most promising, and get in love with a strong hypothesis to join or build a startup around it. This is the hardest part: in an ocean of possibilities, which one to choose? Which one is the most interesting? What technology is the most promising? What are the low hanging fruits?

Mitochondrial mutations - and above all, large deletions in the mitochondrial DNA - accumulate in long-lived cells over our lifetime. And until we can do something to repair or bypass that problem, the overtaking of this small fraction of our cells by deletion-bearing mitochondria will continue to drive diseases of aging. Long before there was a SENS Research Foundation - even before a "Strategies for Engineered Negligible Senescence" (SENS) platform existed - our founding CSO Dr. Aubrey de Grey surveyed the possible solutions for this problem, and the only one that seemed viable was allotopic expression (AE).

So why - after making great leaps forward with the science - are we now breaking ground on entirely new MitoSENS strategies? A few reasons. Considered at the most fundamental level, AE itself is an inherently difficult biotechnological challenge. Then there's the additional hurdle of delivering it to those cells that are vulnerable to mitochondrial mutations with age. Thus scientists in our MitoSENS lab are now working on two of these alternative strategies - both of them also thought up or endorsed by Dr. de Grey. You might think of them as backup strategies for the backup copies.

One of these strategies is to use a form of mitochondrial transplantation to replace the cell's mutation-bearing mitochondria with healthy ones. For mitochondrial transplantation to work as a rejuvenation biotechnology, we need a way not only to get the transplanted mitochondria into the cells, but to enable them to bypass the selective advantage of the native mitochondria, and especially of the powerful advantage of mutation-bearing mitochondria. This is where the relatively new biotechnology of "gene drives" come in. Engineered mitochondria would use restriction enzymes designed to target one of the several restriction sites that are naturally present in the host's mitochondria. The restriction enzyme would quickly go to work eviscerating the cell's original mitochondrial DNA, thereby clearing space to allow the new, transplanted mitochondria to take over.

We can't say much about the second strategy the MitoSENS team is exploring because it's a very early-stage project, and we want to be sure we're on the right track before making any announcements. All we'll say for now is that our scientists have identified a drug that may potentially "unmask" deletion-bearing mitochondria, attracting the attention of the mitophagy machinery and allowing it to cull them. Under some circumstances, such "unmasking" is sufficient to keep deletion-bearing mitochondria at bay when they haven't yet overtaken the cell. If the drug we're testing (or a similar one) could do that, we might be able to keep many cells operating normally by holding deletion-bearing mitochondria down to a minority of the population, and keep other cells free of deletion-bearing mitochondria entirely by catching the first one and sending it to its grave.

Mitochondria are organelles required for the production of ATP. A mitochondrion exhibits semi-autonomous genetic systems, independent genomes, and unique genetic codes that are similar to those found in bacteria. Recently, a short open reading frame (sORF) encoded in the mitochondrial genome has been discovered. These sORF produce bioactive peptides, collectively known as mitochondrial-derived peptides (MDP), which have a wide range of physiological functions and can explain how mitochondria communicate within and between cells in a specific disease environment. Mitochondrial-derived peptides may answer the key biological problems that have plagued the field for decades (such as mitochondrial-nuclear communication, metabolic dysfunction, etc.). Whether in the form of mitochondrial-derived peptide itself or in terms of sORF, mitochondrial-derived peptide is suitable for research as a therapeutic agent.

Mitochondrial-derived peptide called MOTS-c has been shown to significantly reduce the level of pro-inflammatory factors in mice and increase anti-inflammatory factors and insulin-stimulated glucose treatment rates, as well as glucose homeostasis. Furthermore, human studies showed that exercise increased MOTS-c levels in skeletal muscle and blood circulation, indicating that MOTS-c is a mitochondrial-derived peptide induced by skeletal muscle exercise. Additionally, studies have revealed the importance of MOTS-c in regulating obesity and diabetes, longevity, and cardiovascular disease. Specifically, this paper discusses the application of mitochondrial-derived peptides, including MOTS-c, in the treatment of diseases and anticipates the future development direction of MOTS-c combining synthetic biology to provide new ideas on how it can be developed and applied.

Hyperuricemia is defined as an elevated serum uric acid (sUA) level in the blood and is well-known as an independent risk factor for the development of hypertension, metabolic syndrome, and cardiovascular disease. Water is essential to most bodily functions, and its consumption rates appear to decline with age. The aim was to evaluate the influence of water intake on early vascular aging in metabolic middle-aged patients with hyperuricemia.

The study included 241 men aged 40-55 years and 420 women aged 50-65 years from the Lithuanian High Cardiovascular Risk (LitHiR) primary prevention program. Anthropometric characteristics, blood pressure, laboratory testing, and the specialized nutrition profile questionnaire were evaluated. Carotid-femoral pulse wave velocity (cfPWV), assessed using applanation tonometry, was evaluated as an early vascular aging parameter in patients with hyperuricemia and with normal sUA levels.

72.6% of men and 83.1% of women drink insufficient amounts of water (less than 1.5 L per day). However, our results showed statistically significant relationships only among a group of women. The women in the hyperuricemic group had a higher cfPWV than women with normal sUA levels. In hyperuricemic women, drinking less than 0.5 L per day in combination with other risk factors, such as age, increasing fasting glucose, and systolic blood pressure, was statistically significantly associated with an increased cfPWV.

Aging is associated with chronic systemic inflammation largely due to increased myelopoiesis, which in turn increases risk for vascular disease. We have previously shown evidence for the therapeutic potential of Angiotensin-(1-7) (Ang-(1-7)) in reversing vasoreparative dysfunction in aging. This study tested the hypothesis that ischemic vascular repair in aging by Ang-(1-7) involves attenuation of myelopoietic potential in the bone marrow and decreased mobilization of inflammatory cells.

Young or Old male mice of age 3-4 and 22-24 months, respectively, received Ang-(1-7) for four weeks. Myelopoiesis was evaluated in the bone marrow (BM) cells by carrying out the colony forming unit (CFU-GM) assay followed by flow cytometry of monocyte-macrophages. Expression of pro-myelopoietic factors and alarmins in the hematopoietic progenitor-enriched BM cells was evaluated. Hindlimb ischemia (HLI) was induced by femoral ligation, and mobilization of monocytes into the blood stream was determined. Blood flow recovery was monitored and infiltration of inflammatory cells was evaluated by immunohistochemistry.

BM cells from Old mice generated a higher number of monocytes and M1 macrophages compared to that of Young, which was reversed by Ang-(1-7). Gene expression of selected myelopoietic factors, alarmins, and the receptor for alarmins, RAGE, was higher in the Old hematopoietic progenitor-enriched BM cells compared to the Young. Increased expressions of these factors were decreased by Ang-(1-7). Ischemia-induced mobilization of monocytes was higher in Old mice with decreased blood flow recovery and increased infiltration of monocyte-macrophages compared to the Young, all of which were reversed by Ang-(1-7). Enhanced ischemic vascular repair by Ang-(1-7) in aging is largely by decreasing the generation and recruitment of inflammatory monocyte-macrophages to the areas of ischemic injury. This is associated with decreased alarmin signaling in the BM-hematopoietic progenitor cells.

Recently, we proposed the Amyloid Cascade Hypothesis 2.0 (ACH2.0), a reformulation of the original Amyloid Cascade Hypothesis (ACH). In ACH2.0, in contrast to ACH, Alzheimer's disease (AD) is driven by intraneuronal amyloid-β (iAβ) rather than extraneuronal amyloid-β and occurs in two stages. In the first, relatively benign stage, Aβ protein precursor (AβPP)-derived iAβ activates. Then upon reaching a critical threshold, the AβPP-independent iAβ-generating pathway triggers a devastating second stage resulting in neuronal death.

While the ACH2.0 remains aligned with the ACH premise that Aβ is toxic, the toxicity is exerted because of intracellular rather than extracellular Aβ. In this framework, a once-in-a-lifetime-only iAβ depletion treatment via transient activation of BACE1 and/or BACE2 (exploiting their Aβ-cleaving activities) or by any means appears to be the best therapeutic strategy for AD.

Whereas the notion of differentially derived iAβ being the principal moving force at both AD stages is both plausible and elegant, a possibility remains that the second AD stage is enabled by an AβPP-derived iAβ-activated self-sustaining mechanism producing a yet undefined deleterious "substance X" which anchors the second AD stage. The present study generalizes the ACH2.0 by incorporating this possibility and shows that, in this scenario, the iAβ depletion therapy may be ineffective at symptomatic AD stages but fully retains its preventive potential for both AD and the aging-associated cognitive decline, which is defined in the ACH2.0 framework as the extended first stage of AD.

The molecular determinants of lifespan can be examined in animal models with the long-term objective of applying what is learned to the development of strategies to enhance longevity in humans. Here, we comment on a recent publication examining the molecular mechanisms that determine lifespan in worms, Caenorhabditis elegans (C. elegans), where it was shown that inhibiting protein synthesis increased levels of the transcription factor, ATF4. Gene expression analyses showed that ATF4 increased the expression of genes responsible for the formation of the gas, hydrogen sulfide (H2S).

Further examination showed that H2S increased longevity in C. elegans by modifying proteins in ways that stabilize their structures and enhance their functions. H2S has been shown to improve cardiovascular performance in mouse models of heart disease, and clinical trials are underway to test the effects of H2S on cardiovascular health in humans. These findings support the concept that nutrient deprivation, which slows protein synthesis and leads to ATF4-mediated H2S production, may extend lifespan by improving the function of the cardiovascular system and other systems that influence longevity in humans.

We have shown before that at least one intracellular proteolytic system seems to be at least as abundant in the peripheral blood lymphocytes of centenarians as in the same cells of young individuals (with the cells of the elderly population showing a significant dip compared to both young and centenarian cohorts). Despite scarce published data, in this review, we tried to answer the question how do different types of cells of longevous people - nonagenarians to semi-supercentenarians - maintain the quality and quantity of their structural and functional proteins? Specifically, we asked if more robust proteodynamics participate in longevity.

We hypothesized that at least some factors controlling the maintenance of cellular proteomes in centenarians will remain at the "young" level (just performing better than in the average elderly). In our quest, we considered multiple aspects of cellular protein maintenance (proteodynamics), including the quality of transcribed DNA, its epigenetic changes, fidelity and quantitative features of transcription of both mRNA and noncoding RNAs, the process of translation, posttranslational modifications leading to maturation and functionalization of nascent proteins, and, finally, multiple facets of the process of elimination of misfolded, aggregated, and otherwise dysfunctional proteins (autophagy). We also included the status of mitochondria, especially production of ATP necessary for protein synthesis and maintenance.

We found that with the exception of the latter and of chaperone function, practically all of the considered aspects did show better performance in centenarians than in the average elderly, and most of them approached the levels/activities seen in the cells of young individuals.