The Hallmarks of Aging

For thousands of years, people have wondered whether there is a way to avoid the process of aging. Is there such a thing as a "Fountain of Youth"? It has not been until the modern scientific age, however, that scientists have established that aging is probably not just a result of mechanical wear-and-tear on our organs and tissues. "The Hallmarks of Aging" is a review article published in the Journal "Cell" by Lopez-Otin et al. in 2013, Proteostasis describes a state in which the expressed proteins in an organism are in homeostasis, marked by optimal regulation of protein expression, degradation, and their roles in signaling pathways.
Deregulated Nutrient Sensing
Deregulated nutrient sensing is the loss of the cell's ability to detect and respond to nutrient levels, which affects metabolism by altering the balance between catabolism and anabolism leading to age-related obesity, diabetes, and other metabolic syndromes. Molecular pathways involved in nutrient sensing are conserved life span regulators and include caloric restriction, insulin and insulin-like growth factor signalling (IIS) and target of rapamycin (mTOR) signalling.
Mitochondrial Dysfunction
Mitochondrial dysfunction is the creation of dysfunction through the creation of reactive oxygen species (ROS), the effect of hormesis, and the decrease in biogenesis in mitochondria. This often affects oxidative phosphorylation and the amount of energy in the body.
Cellular Senescence
Cellular senescence is permanent growth arrest or the irreversible loss in the ability to divide in somatic cells. This serves a practical purpose as it prevents the division of damaged cells.
Stem Cell Exhaustion
Stem Cells are responsible for the creation and maintenance of the differentiated tissues of an organism. Stem cell exhaustion occurs over time when the stem cells accumulate defects with reproductiona nd lose the ability to proliferate.
Altered Intercellular Communication
Cells communicate with each other by three main mechanisms: neuronal, neuroendocrine, and endocrine. As aging progresses, changes or alterations in these communication mechanisms occur.
Genomic instability: nuclear and mitochondrial DNA
Summary
After Frederick Sanger developed techniques to rapidly sequence DNA in the 1970s, scientists were able to determine the causes of many health conditions and diseases that were previously unknown. Huntington's disease was one of the first genetic diseases to be mapped out and studied. The application of similar experimental techniques for other conditions/diseases revealed that the accumulation of DNA damage was common in biologically older organisms or organisms that demonstrated certain forms of accelerated aging. This damage can take many forms as a result of extrinsic or intrinsic factors. DNA damage that results in aging in multicellular organisms can be categorized into two groups based on the location of the DNA molecules- Nuclear DNA damage (located in the nucleus) and mitochondrial DNA (mtDNA) damage (located in the mitochondria). The Hallmark of Aging review paper identifies both forms of DNA damage as factors which accelerate aging. The paper groups these two forms of DNA damage under the sub-category of the "Genomic instability" hallmark. It is to be noted that, while both DNA and mtDNA are the same structurally, they have different repair mechanisms and are subjected to very different stressors. Nuclear DNA, in general, is considered better protected than its mitochondrial counterpart. The nucleus itself serves as a barrier between the stressors in the cellular environment and the DNA molecule. The nuclear DNA also has telomeres to protect its ends from degradation. Cells have evolved to have very efficient and damage specific DNA repair machineries, which are always employed in preserving the integrity of the DNA. Despite all these protective mechanisms, one of the greatest threats to nuclear DNA is aneuploides, (abnormal number of chromosomes) which is a product of miscommunication during the cell cycle. The presence of an irregular number of chromosomes can impact the competency of the Stem cell<nowiki/>s. Without functional stem cells, tissue renewal becomes hindered in the organism. Mitochondrial DNA lacks the different safety features which nuclear DNA has. It has not evolved efficient DNA repair mechanisms either. Additionally, the mtDNA molecule is constantly exposed to ROS, a byproduct of cellular respiration; this increases its likelihood of accumulating mutations. There is some debate over mtDNA mutations role in aging as mtDNA molecules demonstrate heteroplasmy. However, various studies have shown that individual aging cells have higher amounts of mtDNA mutation load and can even demonstrate heteroplasmy. At the time of publication of the review article, there was no research showing that a reduction in mtDNA mutation load can help extend lifespan.
Research done since the review publication
Since the publishing of “The Hallmark of Aging” review in 2013, many papers have been published on the subject, providing research which further elaborates on the role of the different hallmarks. With the recent advancement in bio-engineering tools and techniques, the field of genetics has especially progressed. This has provided us with a great deal of insightful and interesting information on the genomic instability hallmark.
Previously, there was no reliable simple invertebrate model organism that could be used to study the mtDNA mutation. However, in 2014, Leslie et al. published a paper showing that Drosophila melanogaster can serve as an effective model. The study also demonstrated that Reactive oxygen species are not responsible for the majority of the mtDNA mutations that translate into aging and aging related diseases.While their results are preliminary, and reproducibility of the data must be confirmed, it is definitely promising.
The recent technological progress has also provided scientists with the privilege of working with stem cell<nowiki/>s. This has furthered our understanding of inheritable diseases that are the result of germline mtDNA mutations. It was found that germline mtDNA mutations that lead to respiratory chain (RC) deficiencies are the products of downregulation in the transcription in mtRNAsas well as a reduction in the mtRNAs half life.
It was already known that mtDNA with extensive mutations will often undergo mitophagy; this is obstructed by proteins from the kinase family. Cells with inhibited rapamycin (mTOR) kinase activity supported this hypothesis by demonstrating a reduction in the number of mtDNA mutations, as well as production of more ATP.
Many neurodegenerative diseases are the result of mtDNA mutations. A great deal of research has been done to see how mtDNA mutations cause these conditions and what can we do reduce/diminish their effects. Some rare cases of Alzheimer's disease(AD) and Parkinson's disease (PD) are caused by mtDNA mutations. In general it was found that mtDNA mutation numbers increase,in the brain, in cases of both AD and PD( as well as Down Syndrome and Dementia). It was also found that patients with these conditions have reduced mtDNA mRNA levels, altered mtDNA copy number, and abnormal Aβ metabolism (aka Beta oxidation) in their brain tissues. Discovery of these common variables between the different diseases allows for “common genetic and pathophysiology explanation”, which can then be used to create for efficient treatments.
Dietary restriction is often used to reduce the effects of aging and related diseases. Research was done to examine the impact of dietary restriction on mice with Progeria (resulting in the accumulation of mtDNA mutations). For this, mutant mice were subjected to varying degrees of dietary restriction. It was seen that median and maximum lifespan increased by ~ 200%. Therefore, dietary restriction can aid in counteracting effects mtDNA damage related conditions.
The other theme that is constantly observed as our understanding of the different hallmarks increases, is that, these hall marks are often linked to one another and rarely exist as individuals. Telomere length and mtDNA instability are usually considered independent of one another. But recent research has demonstrated that telomerase, an enzyme that maintains of telomere length, is also responsible for responsible for responding to ROS related stress. In Tyrka et al. the scientists have demonstrated that mitochondrial proliferation and function declined in various tissues of mutant mice with severe telomere damage. The telomere dysfunction in some cases can turn on the p53 pathway.
Genomic instability: nuclear architecture
Summary
Before 2013 and based on the López-Otín et al. "Hallmarks of Aging" review, defects in nuclear architecture have been pointed to as a known cause of aging by various experts in the field. To understand the importance of nuclear lamins, it is key to also understand their role within the cellular nucleus. Nuclear lamins not only protect the DNA from outside factors, but it also has other important purposes, which include "providing a scaffold for tethering chromatin and protein complexes that regulate genomic stability." The peripheral region of the nuclear matrix is known as the nuclear lamina. This region is of high importance for the integrity of the cell because it interacts with inner nuclear membrane proteins, nuclear pore complexes, and peripheral chromatin. The nuclear membrane does not only contain lamins as its main or only component, it is also made up by other scaffolding proteins such as nuclear mitotic apparatus protein, known as NuMA, acting and several actin-binding proteins and less-known matrins or matrin-domain containing proteins. The genes LMNB1 and LMNB2 encode for the B1 and B2 proteins, respectively, and at least one form of lamin B is expressed in every somatic cell. Some of the phenotypes seen in patients diagnosed with nuclear morphological abnormalities include:
# Neuropathies
# Muscular dystrophies
# Lipodystrophies
# Premature aging diseases
Even with thorough understanding of the phenotypes seen in patients with defective lamin genes, the specific relationship between the gene mutation itself and different phenotypes is poorly understood. It has been difficult to determine this relationship because different mutations of the LMNA gene can lead to the same phenotype. Another factor that has intrigued research scientists is to try to understand why laminopathies have been seen to affect a single or few tissues, even when lamin A and lamin C are expressed throughout.
Back in 2003, two different laboratories published their findings relating the mutation of the LMNA gene to be the cause of the Hutchinson-Gilford Progeria Syndrome (HGPS).
This article was published on May 2, 2014 in the Science Magazine journal which is under the American Association for the Advancement of Science (AAAS) organization.
In this article, the researchers aimed the study at finding a way to fix the misshapen nuclei and altered chromatin organization characteristic of diseases associated with cancer and laminopathies, especially the Hutchinson-Gilford Progeria Syndrome (HGPS).
The authors understood that a misshapen nucleus can be detrimental to the cell because it renders the cell fragile and also because such altered shape leads to a downstream effects on chromatin structure, gene expression, DNA replication, or DNA repair. Therefore, their hypothesis was that by restoring nuclear shape, this would improve chromatin structure and ameliorate all of the other side effects, and ultimately see an improved organismal phenotype.
This article was published online on September 27, 2016, in the journal Nucleus.
The article did not look into lamin gene mutation; its focus was the accumulation of prelamin A, the precursor to mature lamin A before it has undergone important post-translational modifications, and its effects in cellular health.
According to the authors, evidence suggests that prelamin A accumulates in cells as an organism ages, specifically in vascular smooth muscle cells. The accumulation of prelamin A has cytotoxic effects, including DNA damage. The relationship between the accumulation of the protein with DNA damage is poorly understood, however.
This research article was published on January 19, 2017, on the journal Scientific Reports.
The authors wanted to explore the mechanism that regulates nuclear shape, and they found a relationship between F-acting cytoskeletal organization and nuclear morphology.
The study finds that cofilin/ADF-family-F-acting remodeling proteins are essential for normal nuclear architecture in different cell types.
According to the review, numerous aspects at the biochemical, cellular and organismal level suggest that telomeres and lamins are more related than previously thought.
Telomeres interact with lamins through telomeric proteins and telomere-associated factors. If an alteration happens to either or both of the structure, cellular decline is bound to be observed.
Through this interaction, the review determines that the study of cellular senescence, a hallmark of aging,
Besides telomerase, another protective measure that telomeres possess is the shelterin complex, which binds to the telomeres, preventing neighboring chromosomes from being joined due to DNA damage repair mechanisms. This complex is of importance because a malfunction of this complex can lead to accelerated aging. Another example was performed in plants, Arabidopsis, and the authors found that telomere dynamics were connected to meristem activity and continuous growth of the plants. Contrasting from humans, plants and zebrafish, the edible dormouse had elongated telomeres as they aged, which was accredited to a reproduction strategy which makes them not reproduce during times of low food. The mechanism by which the edible dormouse elongates its telomeres has not been excessively looked at since the present paper is recent.
Telomere dysfunction/deficiency has been linked to a number of diseases including pulmonary fibrosis. A recent article showed the mechanism by which telomeres affect and lead to the onset of pulmonary fibrosis via the Trf1 gene in mice.
Epigenetic Alterations
Summary
Epigenetic alterations consists of a variety of changes that can occur in the genome. Unlike DNA mutations, these epigenetic alterations are reversible. Examples of epigenetic alterations include DNA methylation, histone modification, and chromatin remodeling. Many enzymes like methyltransferases, (de)methylases, (de)acetylases, and heterochromatin remodeling proteins are under investigation for their ability to alter DNA and their potential to influence lifespan.
Investigation into methylation patterns of the genome during aging suggest that there are various hypermethylated regions that show up through the aging process, which refutes the previous belief that aging was due to a general demethylation of the genome. In addition to this, it has been shown that other environmental factors other than diet, like smoking habits and exercise habits, can affect epigenetics in a way that results in accelerated physiological aging. Furthermore, decreased epigenetic regulation by methylomes has been determined to be reduced with age in human epidermal tissue samples by statistical analyses. Research done by Borman, et al. in 2016 also suggests, in accordance with Horvath, that DNA methylation can be a predictor of age, but in skin tissue. The WRN protein associates with heterochromatin proteins and nuclear lamina proteins that control the structure of the genome. However, Arancio, et al. also notes that the heterochromatic marker H4K20me3 is upregulated in HGPS cells, which marks telomeric heterochromatin, and that "histone H4K16 hypoacetylation is associated with premature senescence." These research highlight the interconnection between different types of epigenetic alterations and between other hallmarks of aging, like telomere shortening, which remind us that aging is a complex process that most likely is not caused by any single phenomenon.
Chromatin Remodeling
As exemplified above, histone modification is intimately associated with chromatin remodeling, since the main units of chromatin are histone proteins on which the DNA is wrapped around to create dense compact chromatin, eventually leading to the most condensed and readily divisible form: chromosomes. Recent study of the effects of chromatin remodeling shows that loss of local interactions between chromatin and TADs (topologically associating domains) or LMNB1 leads to a change in the physical compactness of the DNA unique in senescent cells. LMNB1 is one of four lamin proteins found in the nuclear architecture, and alternative splicing of the mRNA of these genes can lead to defective lamins, causing laminopathies resulting in premature physiological aging.
Loss of Proteostasis
Summary
Loss of proteostasis, as a result of aging, causes defects in the machinery that regulate the proteome of an organism. This can result in a variety of harmful effects on the cell, such as the accumulation of defective proteins, proteins that are not effectively expressed, and defective chaperone proteins. The main enzymes present in this system are known as E1, E2, and E3. E2 is the most central enzyme in this system because it carries out ubiquitin tagging, on proteins that are non-functional. Proteins tagged with ubiquitin are guided into the proteasome complex to be degraded. This process process prevents the aggregation of non-functional proteins, which contributes to aging.
Autophagy-Lysosomal System
Authophagy is the degradation of damaged or non-functional material in the cell, such as organelles or proteins. The process of autophagy is carried out by autophagosomes, and is typically triggered when the cell experiences stress. Autophagy can be carried out in three distinct methods known as chaperone mediated autophagy, macroautophagy, and microautophagy. Inducing the decline of chaperone-mediated autophagy in the hepatic system of mice, caused greater vulnerability to oxidative stress, the inability to metabolize drugs, as well as reduced hepatic function overall. Many studies talk about hormesis, a method which induces moderate quantities of stress to the organism, which can have beneficial effects, such as increased longevity. In this study exposing the model organism, C. elegans, to hormetic heat stress induces autophagy, which becomes less regulated with age. Moderate over-expression of dFOXO in heart tissue of D. melanogaster, resulted in improved protein maintenance mainly in the ubiquitin-proteasome system, but also in the autophagy-lysosomal system. The skeletal muscle samples in older subjects contained 2 fold more protein than the younger subjects. In worms and flies, transcription factor FOXO has shown to be relevant to aging, but little was known about the four FOXO members in mice. Knocking down a component of mTORC1, such as S6K1 was also sufficient to extend lifespan. The addition of rapamycin also increased longevity in mice. AMPK senses low nutrient levels and catabolism through the presence of AMP.
Research done since the review publication
Since the publication of the “Hallmarks of Aging” review, the components of deregulated nutrient sensing have been investigated further. More information in regard to pathway components are currently being researched with the hope of better understanding the causes of deregulated nutrient sensing and its contribution to the aging phenotype. More treatments can be developed to protect against age-related disease when new information is discovered. A common trend is the interconnection of the hallmarks. The more research that is done, the more connections seem to be made. Below are some advances made since the "Hallmarks of Aging" review. Specifically, the mechanisms underlying caloric restriction and the AMPK pathway were further investigated. Additionally, sirtuins, briefly mentioned in the review, and sestrins, not mentioned at all, were found to play a large role in deregulated nutrient sensing.
Caloric Restriction
The processes behind the effects of caloric restriction on longevity have been further investigated. Caloric restriction is defined as consuming fewer calories, but not to the extent of malnutrition. In particular, activating FOXO has been shown to play a role in the telomere attrition hallmark through improving telomerase activity, showing again how the hallmarks are connected. Specifically, carbohydrates and protein levels dictate dietary intake. Manipulating dietary adenine could alter metabolism to influence lifespan. In particular, one member of this family, sirtuin 1 (SIRT1), is an NAD deacetylase. However, little was known about the mechanism. Obese mice deficient in sestrins were shown to get diabetes sooner than mice without the deficiency. Conversely, Sensn3 transgenic mice were protected against these disorders, even with a high-fat diet.
Although it was previously thought that outside treatments that were mildy toxic had a harmful effect on organelles, it might actually be beneficial to them. This is called mitohormesis and may actually cause an increase in cellular functioning. Therefore, treatments that would originally damage the cell and the mitochondria and cause a small amount of dysfunction in oxidative phosphorylation can actually promote lifespan.
Biogenesis is the creation of organelles. Increased biogenesis has been found to reduce aging by promoting healthy aerobic respiration. Mitochondria are always undergoing biogenesis. One gene that primarily controls this process is the peroxisome proliferator-activated receptor γ co-acticator 1α (PGC-1α). The expression and post-translational modification of this gene induces nuclear respiratory factors which are partially responsible for nuclear-encoding mitochondrial proteins. Biogenesis is especially important in skeletal muscle cells in which great amounts of energy are used in a single period.
Research done since the review publication
Since the Hallmarks of Aging paper
An additional study performed on Drosophila melanogaster studied the knockdown of mitochondrial ATP synthase subunit d (ATPsyn-d). This knockdown has demonstrated the ability to promote longevity. It is also shown that it is also associated with improved protein homeostasis and increased resistance to oxidative stress. It is suggested that it selectively alleviates oxidative damage from the mitochondria to maintain homeostasis in the cell and can vary in response based on acute or chronic stress and diet. The knockdown longevity is highly influenced by a high protein low carbohydrate diet. These effects were not seen in male Drosophila, which could be due to gender differences in physiology and nutrient uptake.
Another study done by Fleenor et al. (2013) showed that the spice, curcumin, has been found to reduce oxidative stress, improve vascular function, and increase lifespan. Curcumin comes from the plant Curcuma longa. This plant works by creating levels of the mitochondrial antioxidant enzyme manganese superoxide dismutase (MnSOD) which reduces oxidative stress. Cucumin was also found to scavenge for free radials, another potential cause of aging.
The lifespan of Caenorhabditis elegans has been shown to increase when parts of the ETC have been diminished in activity. Mishur et al. (2016) created a specific mitochondrial mutant (Mit) that demonstrates these effects. It is seen that the effects of longevity on Mit mutants requires hypoxia-inducible factor-1 (HIF-1). HIF-1 is a protein with α and β subunits that helps with transcription in hypoxic conditions. Without this protein all effects are abolished even under normal respiration conditions. α-ketoglutarates are found to regulate HIF-1 and can accumulate in Mit mutants. These metabolites that accumulate after mitochondrial dysfunction directly affect the lifespan of the cell by increasing HIF-1.
More research has also been done on the effects of mitohormesis and ROS in the mitochondria using the drug, Metformin. Through the process of mithormesis, metformin increases the amount of ROS. This produced a decrease in the affect of aging in Caenorhabditis elegans, Rattus norvegicus, and Mus musculus. The affect on lifespan mimics a caloric restriciton model. Metformin inhibits complex 1 of the ETC causing electron flow to slow down and breathing rate to increase. After ROS are created they can go on to form hydrogen peroxide. Peroxiredoxins help alleviate the harsh affects of hydrogen peroxide, by scavenging for these molecules.
Exercise has also been found to have a profound affect on mitochondrial health. A study conducted on rats observed immobile young and old rats as well as active rats and looked at their PGC-1α mRNA and nuclear PGC-1α protein, This mRNA and nuclear protein are used to help stimulate mitochondrial DNA replication and transcription, which helps provide the mitochondria will the tools it needs for oxidative phosphorylation. Low levels of these were cognisant of age in the old immobile rats however some of these effects were reveresed in the old active rats demonstrating the endurance exercise can reverse or slow the affects of aging in skeletal muscle. These means of causing cellular senescence occur as one ages. Due to the build-up of senescent cells increasing with age it has been hypothesized that cellular senescence is related to aging as the accumulation of the senescent cells may exasperate DNA damage by secreting proinflammatory secretome. The INK4a/ARF locus encodes for the p16 and p53 pathways. Other research suggests that cellular senescence is the leading cause for age related lung diseases in the elderly. Current research has shown that silencing small GTPase DIRAS3 can affect and induce cellular senescence in adipose stromal/progenitor cells and how this could be a way to control and prevent obesity and thereby extending lifespan. Researchers have also found that MicroRNA-29 can induce cellular senescence in aging muscles and increase the cell arrest proteins like p53, as mentioned in the Hallmarks of Aging review. Interestingly resveratrol has also been recently studied as a way to induce cellular senescence in cancer cells and how the effects of RSV could potentially be used as a form of cancer treatment. Whilst many avenues of cellular senescence is being researched, many researchers can agree that it is important to understand cellular senescence and it role on aging to potentially find ways to extend lifespan.
Stem Cell Exhaustion
Summary
Stem cells are undifferentiated cells, meaning that they do not have a specific function. Stem cells are important in maintaining tissue and organ function because as specific cells are damaged stem cells become specialized and replace the worn-out cells in the organism. Over time DNA damage, caused by mistakes, in the process of DNA replication, causes stem cells to become exhausted and cease replication. This inability to replicate and form new specialized cells causes damage to organs and tissues because there are no new cells to replace the damaged or worn down cells in the organism. This damage and wearing down of tissues and organs lead to aging in the organism.
Research done since the review publication
Since 2013, when the "Hallmarks of Aging," there has been major research into exactly what stem cells effect and how the body, as a whole, responds. This research has focused on such topics as classic telomere length, shown in a 2015 study "Telomere Dysfunction Causes Alveolar Stem Cell Failure." Other studies have shed light onto processes that were previously thought to be unaffected such as looking at DNA methylation and different pathways that hadn't been explored. These studies include "Proliferation-Dependent Alterations of the DNA Methylation Landscape Underlie Hematopoietic Stem Cell Aging" and "Loss of aryl hydrocarbon receptor promotes gene changes associated with premature hematopoietic stem cell exhaustion and development of a myeloproliferative disorder in aging mice." These studies show a change in research conducted since the 2013 "Hallmarks of Aging" was published.
The article “Proliferation-Dependent Alterations of the DNA Methylation Landscape Underlie Hematopoietic Stem Cell Aging" published by Beerman is significant because this article tackles many different hypothesizes that were discussed in the 2013 article but not researched. One of the major findings from this article is that telomere length is independent of stem cell DNA methylation and age-related problems. This study focused on the reasons for stem cell loss of function with regards to aging wild types. They discovered the Enhancer of zeste homolog 2 (Ezh2) which was found to be the most expressed transcript in hematopoietic cells. They then overexpressed Ezh2 and found that they could overcome cellular senescence and they conserved repopulating potential, of the stem cells, long after the wild-type cells had been exhausted. They concluded that this Ezh2 helped with stabilization that helped conserve the stem cells from stress related to aging. This study focused on the Arf/p53 pathway and how its role in cancer suppression is affected by quantity and age. They found that increasing p53 delays stem cell exhaustion and decline of homeostatic tissues. However, they also observed that if p53 is being constantly activated then the pathway accelerates the aging process of stem cells which reduces tissue regeneration and replicative regulation. found that cancer stem cells (CSCs) can regenerate all the parts of the tumor and unless destroyed can regenerate all of the affected cells. This study aimed to examine what exactly contributed to CSCs ability to proliferate and their maintenance.<ref name=":32" /> This study found that the more damage, caused by DNA methylation and incorrect RNA editing and splicing allowed for these CSCs to form and from them allowed all facets of the tumor to proliferate.<ref name=":32" />
Altered Intercellular Communication
Summary
As aging progresses, changes or alternations in intercellular communication occur. These intercellular communications consist mostly of three types. The first type is neuronal which consists of communication that only happens between the cells of the nervous system, specifically the neurons. The second type is neuroendocrine which consists of communication that happens between the nervous system neurons and the endocrine system's hormones. Last is endocrine which consists of communication that only happens between the cells of the endocrine system. Any of these three types of communication can be affected in the process of aging. Research has shown that altered intercellular communication due to aging leads to increased inflammation, reduced neurogenesis and decline in efficient autophagy.
Research done since the review publication
Previous research done by Zhang et al. in 2013 found that the inhibition of IκB kinase-β, IKK-β, and nuclear factor κB, NF-κB, in the hypothalamus caused an increase in gonadotropin-releasing hormone, GnRH, which led to adult neurogenesis. Thus, Zhang et al. were cited in “The Hallmarks of Aging” under altered intercellular communication for their findings. Later research after 2013 also agreed with Zhang et al. that IKK-β and NF-κB is an integral part of aging and longevity. In recent years, research in altered intercellular communication in regards to aging and longevity has shifted from studying the neuronal network into examining how the circadian rhythm and cycle affects the hippocampus and neurogenesis.
However, circadian rhythm and cycle was not the only aspect being studied. Research was also conducted on various receptors, proteins, and hormones that had a connection to the effects of altered intercellular communication to see if they were the cause, effect, or otherwise. In addition, these receptors, proteins, and hormones were examined and manipulated extensively to see if they were able to improve the effect of altered interceullar communication or not. In early 2017, Lacoste et al. proposed the malfunction or impairment of the circadian clock as the tenth hallmark of aging. They suggested that aging, the circadian clock and cellular oxidative stress are interrelated, because they propose decrease efficiency of the antioxidant defense system with age. However, some of their findings about the levels of lipoperoxidation, LPO, and glutathione, GSH, as a factor of measuring oxidative stress as a person ages does not agree with earlier research. The reason behind this is still hugely unknown until further research has been conducted.

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