Alexey Rzheshevsky

Alexey Rzheshevsky


NF-κB and aging: multiple complexity

Everyone who is interested in the fight against aging has probably heard about age-related inflammation (inflammaging). And also about the key molecule of these processes, the transcription factor NF-κB. Over the past couple of decades of active study of NF-κB, a number of animal and cell culture experiments have been conducted, as well as genetic defects that affect the functioning of NF-κB in humans have been studied. Here we have tried to collect all the most important things regarding this factor and aging. NF-κB is an evolutionarily ancient, structurally complex and multifunctional molecule that we truly admire because of its beauty, ubiquity and functional diversity. Let’s remember what this NF-κB is.


What is NF-κB?

General information about the NF-κB protein, its encoding genes and biodiversity

The full name of the factor, given to it upon discovery, is as follows: Nuclear Factor Binding Near the κ-light-chain gene in B cells. As Nobel laureate David Baltimore, who discovered NF-κB, wittily admitted in one of his papers, “if we had known then that NF-κB would play such an important role in inflammation and other normal and pathological processes, we would have given it some more simple title1.

NF-kB regulates the expression of many genes associated with various biological processes, including immune response, cell proliferation, and apoptosis. It is expressed almost ubiquitously. In cells, NF-κB is present as homodimers or heterodimers .

In vertebrates, NF-κB dimers are formed from five proteins. They, in turn, are divided into two groups (Fig. 1):

  • one subfamily is called “NF-kB proteins”. And it consists of NF-κB1/p50 and NF-κB2/p52 proteins. A characteristic feature of the proteins of this group is the C-terminal IkB-like inhibitory domains. They must be removed for the proteins to become active.
  • the second subfamily, Rel proteins, consists of proteins with C-terminal transactivation domains (TAD) and includes c-Rel, RelA (p65) and RelB2.

All NF-κB proteins share a similar N-terminal DNA binding and dimerization region, the Rel homology domain (RHD). It contains a nuclear localization sequence (NLS), which allows RHD proteins to enter the nucleus and bind to specific DNA regions, activating or repressing the transcription of target genes. Five proteins (subunits) combine with each other to form different dimeric NF-κB molecules. Classical pro-inflammatory NF-κBs are heterodimers of RelA/p50 (it was this that was first discovered as NF-κB by D. Baltimore in 1986) and c-Rel/p50. Not all subunits can form stable NF-kB dimers. And out of 25 possible variants, 15 different NF-kB complexes are known today. But that’s not all. In addition to dimerization, the molecules undergo such modifications as phosphorylation of serine, threonine, and tyrosine residues, and polyubiquitination3.

Fig.1. Schematic diagram of NF-κB family members. Members of the NF-κB family share a common n-terminal Rel homologous domain (RHD). Which is responsible for binding to DNA. The p65 family members, c-rel, and RelB contain a transactivation domain (TAD), which up-regulates gene expression. Transcriptional suppressor family members p52 and p50 contain glycine-rich regions (GRRs) that are required for their proteolytic cleavage. As well as ankyrin repeats similar to those found in NF-κB inhibitor proteins, IκB. Due to which p52 and p50 can act as cytoplasmic inhibitors of NF-κB.

In an inactive state, NF-kB rests quietly in the cytoplasm of cells bound to its inhibitor, IkB. And only a small pool of NF-κB is present in the nucleus under homeostatic conditions to maintain the transcription of a certain number of genes. Upon extracellular stimulation or stress, IκB is degraded to release NF-κB. It travels to the nucleus and binds there to specific DNA-binding motifs. The expression of hundreds of target genes is thus modulated. More than 150 different NF-κB inducers and more than 400 of its target genes are known in vertebrates, according to Claudio Franceschi and colleagues in “Constructing an Interactome Mapping of NF-κB Pathways”4.

In a commemorative article published 30 years after the discovery of NF-κB, Baltimore was still perplexed to remark that it was amazing how he, NF-κB, managed to do everything in a coordinated manner with so many targets and inductors.

В юбилейной статье, опубликованной спустя 30 лет после открытия NF-κB, Балтимор все ещё недоуменно отмечал, что просто удивительно, как это ему, NF-κB, все удается делать скоординировано, при таком большом количестве мишеней и индукторов.

NF-κB's remarkable ability to alter cell biology is due to the hundreds of target genes that it activates or represses. Even with 15 potential forms, this is a difficult task, because each component is needed in a certain concentration and at a certain time after exposure. The central question remains open: how can a fairly simple regulatory system respond to a huge group of inducers and accurately translate their signal into appropriate patterns of gene expression in various tissues?1

David Baltimore

Baltimore adds a fly in the ointment to our optimism about the data obtained from animal models.

It is striking how often the effects of (NF-κB) in humans differ from those in mice when comparing similar or even identical mutations. This is evidence of how evolution used these proteins differently in the two species. In many cases, we do not know exactly what these differences are: they can be quantitative or qualitative. Because NF-κB is involved in infection control, and the pathogens affecting humans and mice are very different, evolution seems to have adapted to the exact requirements of the two species. If one could work with more species, then there would probably be an increasing richness of specificity.

David Baltimore

Baltimore also points to the need for caution in the use of NF-κB inhibitors in practice, since it is necessary for the work of immune cells that recognize and kill mutated counterparts. All of this greatly complicates NF-κB research.

Biochemical pathways for NF-κB activation

Biochemists today identify three pathways for NF-κB activation. The first one is classic. Signals associated with damage or infection (from pro-inflammatory cytokines, bacterial lipopolysaccharides, etc.) lead to the activation of the IκB kinase (IKK) complex, consisting of IKKα (IKK1), IKKβ (IKK2) and the main modifier NF-κB (NEMO, or IKKγ ). This promotes proteasomal degradation of the NF-κB inhibitor, IκBα. NF-κB is released and moves into the nucleus. There it activates numerous pro-inflammatory cytokines (TNFα, IL-1, IL-6, IL-12), chemokines (CXCL1, CXCL2, RANTES) and adhesion molecules involved in inflammatory processes.

The second way of activation is non-classical. Here, members of the TNF receptor superfamily such as LTβR, BAFFR, CD40L and RANK can act as activators.

The third pathway of NF-κB activation is atypical. In it, various stress factors are involved in the processes of NF-κB activation. For example, ultraviolet and ionizing radiation, hypoxia and an increase in the production of ROS

Biochemists today identify three pathways for NF-κB activation. The first one is classic. Signals associated with damage or infection (from pro-inflammatory cytokines, bacterial lipopolysaccharides, etc.) lead to the activation of the IκB kinase (IKK) complex, consisting of IKKα (IKK1), IKKβ (IKK2) and the main modifier NF-κB (NEMO, or IKKγ ). This promotes proteasomal degradation of the NF-κB inhibitor, IκBα. NF-κB is released and moves into the nucleus. There it activates numerous pro-inflammatory cytokines (TNFα, IL-1, IL-6, IL-12), chemokines (CXCL1, CXCL2, RANTES) and adhesion molecules involved in inflammatory processes.

The second way of activation is non-classical. Here, members of the TNF receptor superfamily such as LTβR, BAFFR, CD40L and RANK can act as activators.

The third pathway of NF-κB activation is atypical. In it, various stress factors are involved in the processes of NF-κB activation. For example, ultraviolet and ionizing radiation, hypoxia and an increase in the production of ROS

Biochemists today identify three pathways for NF-κB activation. The first one is classic. Signals associated with damage or infection (from pro-inflammatory cytokines, bacterial lipopolysaccharides, etc.) lead to the activation of the IκB kinase (IKK) complex, consisting of IKKα (IKK1), IKKβ (IKK2) and the main modifier NF-κB (NEMO, or IKKγ ). This promotes proteasomal degradation of the NF-κB inhibitor, IκBα. NF-κB is released and moves into the nucleus. There it activates numerous pro-inflammatory cytokines (TNFα, IL-1, IL-6, IL-12), chemokines (CXCL1, CXCL2, RANTES) and adhesion molecules involved in inflammatory processes.

The second way of activation is non-classical. Here, members of the TNF receptor superfamily such as LTβR, BAFFR, CD40L and RANK can act as activators.

The third pathway of NF-κB activation is atypical. In it, various stress factors are involved in the processes of NF-κB activation. For example, ultraviolet and ionizing radiation, hypoxia and an increase in the production of ROS5 (Fig. 2).

Fig.2. Canonical and non-canonical pathways of NF-κB activation. In the canonical pathway, dependent on the major modulator of nuclear factor-κB (NEMO), IKK kinases are activated by tumor necrosis factor receptor (TNFR), cytokines, and Toll-like receptors (TLRs). Activation of the IKK complex induces proteasome-mediated proteolysis of inhibitory proteins, IκB. This allows the NF-κB complex to accumulate in the nucleus. NF-κB dimers bind to DNA and regulate the transcription of target genes.
In a non-canonical NEMO-independent pathway, NF-κB inducing kinase (NIK) phosphorylates IKKα and results in p100 phosphorylation. This process causes subsequent ubiquitination and partial degradation of p100 by the proteasome to form the NF-κB complex (p52/RelB).

There is also an anti-inflammatory version of this factor. It contains the NFKB1 subunit (p105/p50), which forms homodimers with anti-inflammatory activity. In a number of experiments with mice, Nfkb1 knockout has been shown to cause increased inflammation, DNA damage, and premature aging6 7 8 9.

How the evolutionary history of NF-κB genes explains their biodiversity

Evolutionarily, NF-κB is very ancient and conservative. Genes encoding NF-κB proteins have been found in vertebrates, insects, cnidarians (such as hydras), sponges, and unicellular organisms. The most ancient NF-κB-like proteins are believed to have appeared about a billion years ago, at the border of the transition from unicellular to multicellular. Then, 500 million years later, a duplication of the gene encoding NF-κB proteins occurred. As a result, one of the copies gave rise to a new subfamily, the Rel proteins. Notably, NF-κB proteins were not found in the nematode Caenorhabditis elegans, a known model organism. At the same time, retroviruses such as Rev-T, which contains the v-Rel protein from the same Rel protein family, have them2 10.

The biological role of NF-κB in protists (unicellular and protozoan multicellular organisms) is still not fully known. It can be assumed that it is very different from that performed by NF-κB in multicellular animals, because protists do not have innate and adaptive immunity with specialized immune cells. In protozoan symbiotic organisms, NF-kB can modulate protist or host immunity to facilitate symbiosis. 11 12

As one of the pioneers in the study of NF-κB, the American geneticist Thomas Gilmore, writes in his work, after years of research, some questions regarding the evolution of this factor remain unclear.

What was the simplest organism with an NF-kB-like transcription factor? What was the original biological process controlled by NF-kB? Was it a primitive immune-like response, which seems to be the main function of NF-kB in organisms ranging from arthropods to mammals? What proteins were included in the original NF-κB pathway? Can NF-kB activity be used as a "symptom" of disease or stress in invertebrates in the same way that NF-kB activation is associated with countless human inflammatory diseases? It can be assumed that the results of future studies will reveal additional important biological processes controlled by this transcription factor, which plays such a pervasive role in human physiology and disease.

Tom Gilmour

It’s hard to disagree with this. The role is truly pervasive11.

What is the role of NF-κB in the body?

The main biological function of NF-κB is to change cellular programs in various stressful situations. This is necessary so that different types of cells can respond to stress in the right way and the body can cope with the threat, activate defense mechanisms and eliminate dangerous factors.

Target genes that are activated by NF-κB include a variety of cytokines and chemokines. Most of them themselves activate NF-κB, thus forming a positive feedback loop. Another set of NF-κB-activated genes encodes adhesion molecules. They play a crucial role in the movement of leukocytes through the endothelium and in the formation of intercellular interactions important for immune defense and platelet function12 (Fig. 3).

Fig.3. NF-κB as a central regulator of transcriptional responses to a wide range of physiological and environmental stimuli. Signals ranging from pro-inflammatory cytokines to stress including reactive oxygen species (ROS), ultraviolet light (UV) and DNA double-strand breaks (DSB) to antigen receptor involvement lead to NF-κB activation. Several inherited and somatically acquired mutations can also lead to NF-κB activation. Upon activation by various stimuli, NF-κB induces the expression of a wide range of genes. These transcriptional programs have far-reaching biological implications and include survival factors, growth factors, cytokines, chemokines, numerous major mediators of adaptive and innate immunity, and microRNAs.

At the cellular level, NF-κB activation leads to the activation of anti-apoptotic genes. This supports cell survival under stress. In addition, NF-κB activates the proteins cyclin D and the c-Myc oncogene, which activate many cell cycle proteins13.

In addition to this, NF-κB activates other transcription factors. For example, members of the IRF family that regulate interferon and are required for immune defense. As well as HIF-1α, GATA-3 and LEF1, with a complex effect on the cellular transcriptional network and the formation of numerous feedback loops. The complexity of all feedback chains is enhanced by NF-κB-dependent activation of several miRNAs, which suppress the translation of many mRNAs, preventing protein synthesis14 (Fig. 4).

Fig.4. NF-κB target genes involved in the development and progression of inflammation. NF-κB can activate the transcription of various genes and thereby regulate inflammation. NF-κB affects inflammation not only directly by increasing the production of inflammatory cytokines, chemokines, and adhesion molecules, but also by regulating cell proliferation, apoptosis, morphogenesis, and differentiation.

An important role in NF-κB activation is played by counteracting negative feedback mechanisms, which are also induced by NF-κB. This is logical – after the threat is eliminated, all immune and related processes should be stopped. Violation of this rule often underlies chronic diseases associated with inflammation.

Why is studying NF-κB important for anti-aging?

Let’s see how NF-κB can be involved in the aging process.

In 2003, the famous British biochemist Nick Lane put NF-κB at the head of his theory of aging – the theory of double action (or double-agent theory, double-agent theory). In it, he combined the three most popular theories of aging:

  • the disposable soma theory;
  • theory of antagonistic pleiotropy;
  • free radical theory.

The key process underlying the dual action theory is the reversible increase in oxidative stress and the associated change in redox potential. It is necessary to trigger a stress and inflammatory response in response to numerous damaging factors. Numerous transcription factors involved in the stress response (including NF-kB, SoxRS, OxyR, AP-1, Nrf2, and P53) are sensitive to changes in redox potential. This means that their activity is regulated, among other things, by groups such as thiols, which can be oxidized or nitrosylated by free radicals of nitrogen and oxygen (Fig. 5).

Fig. 5 Activation of NF-κB during aging by ROS. Aging is associated with increased production of reactive oxygen species (ROS). ROS can cause DNA damage. The DNA damage response (DDR) process induces NF-κB activation via ATM kinase. Also, ROS can directly affect downstream targets by activating the IKK complex. In addition to affecting IKK, ROS can alternatively activate the NF-κB complex via the Syk–CKII signaling pathway, by phosphorylation of IκBα. Phosphorylation of p65 at serine residues, S276, by ROS also leads to an increase in NF-κB activity.

Lane compares free radicals to fire smoke. It activates the “smoke detector” (in our case, the transcription factor) in case of infectious or other physiological stress. The smoke detector in turn “calls” the fire brigade (stress and inflammation response) to put out the fire (remove infection and damage in the body).

As we age, oxidative stress is known to gradually increase. It turns out that there is smoke, but no fire – there are free radicals, but no infection. However, the “fire department” is activated to destroy the phantom target. The same transcription factors that activate the body’s response to stress and infection cause a shift in gene expression during aging. Because oxidative stress in aging is protracted, chronic, and self-perpetuating, inflammation stimulated by reactive oxygen and nitrogen species also becomes chronic, further exacerbating oxidative stress. In this situation, one of the manifestations of antagonistic pleiotropy is clearly visible – when the negative effects of oxidative stress appear in old age. They don’t disappear by natural selection.17

The description made by N. Lane 20 years ago is very important for understanding the role of inflammation and NF-kB in aging, with one exception. In 2003, our knowledge of the pathophysiological function of NF-kB was still very limited. Today, we can say that, apart from mitochondrial dysfunction and oxidative stress, all other major mechanisms and signs of aging are also closely related to NF-kB. They either progress with it or increase its activity. Or both occur, resulting in a positive feedback loop. We list these main mechanisms (Fig. 6):

  • genomic instability;
  • mitochondrial dysfunction;
  • cellular aging;
  • disturbance of perception of nutrients;
  • shortening of telomeres;
  • depletion of the stem cell pool;
  • epigenetic changes;
  • transposon activation;
  • accumulation of final products;
  • glycation (AGE) and aging;
  • extracellular matrix;
  • activation of the renin-angiotensin system.
  • autophagy dysfunction
  • dysregulation of circadian rhythms.

Fig.6. Schematic illustration depicting NF-κB as a central factor in the processes of aging and longevity.Growth-promoting survival pathways known to promote aging phenotypes, specifically insulin/IGF-1 and mTOR, stimulate NF-κB as described. Insulin/IGF-1 acts through two mechanisms, AKT and mTOR signaling, to activate NF-κB. Along with this, through AKT, insulin/IGF-1 signaling also interacts with known longevity processes by inhibiting the FOXO signaling pathway. Meanwhile, SIRT and calorie restriction (CR) as well as FOXO inhibit NF-κB signaling. In addition, the body’s response to stress and injury contributes to age-related changes, including genotoxic stress, ROS, and inflammation. All of these factors also activate NF-κB. In turn, NF-κB then promotes aging-related changes by promoting cellular senescence, SASP, and inflammatory responses.

All of them are somehow associated with an increase in NF-κB activity. Let us consider further the main of these relationships.

The first description of NF-κB activation during aging was made 10 years after its discovery, in 1996. Then M. Helenius and colleagues found a noticeable increase in the DNA-binding activity of NF-κB in myocardial cells in old mice15.

In 2007, Adam Adler and colleagues conducted a large study with several types of human and mouse tissues and showed that NF-κB is the main transcription factor that regulates the expression of genes associated with aging16.

Research on NF-κB in the context of aging received particular attention in 2013. Then the famous work of D. Kai and co-authors was published in Nature under the title “Hypothalamic programming of systemic aging with the participation of IKKβ/NF-κB and GnRH”. In it, the authors described how inflammation of the hypothalamus and activation of the NF-κB pathway cause a decrease in gonadotropin-releasing hormone levels and systemic aging17.

After these discoveries, few doubted that NF-κB plays a critical role in aging. This has also been shown in a number of experiments on animal models of accelerated aging. Let’s talk about some of them.

Why does NF-κB activity increase and how can it be prevented?

It is appropriate to recall that longer-lived species have two common features compared to less long-lived species – increased activity of signaling pathways associated with DNA repair and reduced levels of inflammation18 19 20 21 22 23.

How does DNA damage affect NF-kB and subsequent inflammation? Today this process is already well described.

When cells are exposed to agents that cause DNA damage, an evolutionarily conserved signaling response called the DNA damage response (DDR) is activated. This response can induce both canonical and non-canonical NF-κB activation involving ATM kinase and NEMO protein. At the same time, ATM kinase is considered to play a critical role in NF-κB activation under genotoxic stress, as one of the main regulators of DDR. It happens like this: genotoxic stress induces ATM activation and NEMO translocation to the cell nucleus. There, ATM and NEMO are combined into a complex. Then the ATM-NEMO complexes move to the cytoplasm, where they activate the next signaling complex, IKK kinases, after which the canonical activation of NF-κB is triggered (we described it above)24 25.

In addition, ATM kinase stimulates the activity of the transcription factor GATA4, promoting GATA4-dependent activation of NF-kB. How does this happen? ATM enhances the stability of GATA4 during DDR passage by inhibiting autophagy-dependent degradation of GATA4. In turn, GATA4 stimulates long-term NF-κB activation through transcription of key genes in this process, such as TRAF3IP2 and IL1A, which are critical factors in initiating and maintaining NF-κB signaling26.

Quite revealing studies have been carried out on mice with a knockout of the Lmna and Zmpste24 genes. They encode lamin A and zinc metalloproteinase involved in post-translational modification, the formation of mature lamin A, respectively. The fact is that lamins A are expressed in an immature form – in the form of prelamins. For maturation, they need to undergo multiple post-translational modifications of the carboxyterminal CAAX motif (where C is cysteine, A is an aliphatic amino acid, X is any other amino acid). During them, 15 amino acids are removed from prelaminin A using Zmpste24 metalloproteinase27.

Mutations in the genes Lmna and Zmpste24 are responsible for several human progeroid syndromes, collectively referred to as “progeroid laminopathy”. These are, for example, Hutchinson-Gilford syndrome, atypical Werner syndrome, restrictive dermopathy and mandibuloacral dysplasia. Today we know that changes in the nuclear envelope also occur during normal aging28.

Mice without Zmpste24 and Lmna are used in Hutchinson-Gilford syndrome studies because they recur most of the progeroid manifestations present in patients with this progeria. Using these animal models, the famous team of C. López-Autin, who first described the classic nine signs of aging, found29 that NF-κB activation is the link between nuclear plate defects, systemic inflammation, and progeroid phenotypes. At the same time, genetic or pharmacological blockade of NF-κB significantly increased the lifespan of Zmpste24 and Lmna knockout mice30 31.

Important studies have been carried out on mice with a knockout of one of the NF-κB subunits, Nfkb1. We have already mentioned it earlier in connection with its anti-inflammatory effects. Mice lacking Nfkb1 exhibited hyperactivation of the pro-inflammatory NF-κB dimer, increased systemic inflammation, increased oxidative stress, and shortened telomeres. They developed alopecia, skeletal abnormalities, which once again proves the leading role of NF-κB in the aging process. In addition to progeroid and mutant animal models, NF-κB blockade also increased lifespan in normal fruit flies9 8 6 32.

A number of studies have shown that NF-κB is activated with aging through known signaling pathways for insulin/insulin-like factor, mTOR, and the renin-angiotensin-aldosterone system (RAAS). At the same time, calorie restriction, metformin, resveratrol, and rapamycin exert their beneficial effects by inhibiting, among other things, NF-κB activity.

In a 2021 paper, the team of renowned gerontologist Nir Barzilai showed the relationship of NF-kB and protein kinase C (PKC) signaling pathways to longevity in humans. They analyzed 700 genes potentially associated with aging using data from 450 centenarians. Scientists have identified three genes that have the greatest impact on longevity in humans. These are the genes for clusterin CLU (which reduces the risk of Alzheimer’s disease and suppresses NF-kB activity), the NF-kB inhibitor NFKBIA, and one of the protein kinases C, PRKCH. As the authors write, variants of these genes in centenarians suppressed the activity of NF-kB and PKC signaling pathways. Moreover, for all these genes separately, the relationship with aging was previously shown in animal models. Finally, the same was confirmed in a large sample of centenarians33 34 35 36.

Почему повышается активность NF-κB и как это предотвратить?

Уместно напомнить, что более долгоживущие виды имеют две общие характерные особенности по сравнению с менее долгоживущими видами – повышенную активность сигнальных путей, связанных с репарацией ДНК и пониженный уровень воспаления.37 38 39 40 41 42

Как же повреждение ДНК воздействует на NF-kB и последующее воспаление? Сегодня этот процесс уже достаточно хорошо описан.

Когда на клетки действуют агенты, вызывающие повреждение ДНК, активируется эволюционно консервативный сигнальный ответ, который называется реакцией на повреждение ДНК (DDR). Этот ответ может индуцировать как каноническую, так и неканоническую активацию NF-κB с участием киназы ATM и белка NEMO. При этом считается, что киназа ATM играет критическую роль в активации NF-κB при генотоксическом стрессе, в качестве одного из основных регуляторов DDR. Происходит это так: генотоксический стресс индуцирует активацию АТМ и перемещение NEMO в ядро клетки. Там АТМ и NEMO объединяются в комплекс. Затем комплексы ATM-NEMO перемещаются в цитоплазму, где они активируют следующий сигнальный комплекс — киназы IKK, после чего запускается каноническая активация NF-κB (ее мы описали выше).24 43

Помимо всего, киназа ATM стимулирует активность транскрипционного фактора GATA4, способствуя GATA4-зависимой активации NF-kB. Каким образом это происходит? ATM повышает стабильность GATA4 во время прохождения DDR за счет подавления зависимой от аутофагии деградации GATA4. В свою очередь, GATA4 стимулирует долговременную активацию NF-κB посредством транскрипции ключевых в этом процессе генов, таких как TRAF3IP2 и IL1A, которые выступают критическими факторами в инициации и поддержании передачи сигналов в пути NF-κB.44

Довольно показательные исследования были проведены на мышах с нокаутом генов Lmna и Zmpste24. Они кодируют ламин А и цинковую металлопротеиназу, участвующую в посттрансляционной модификации, образовании зрелого ламина А, соответственно. Дело в том, что ламины А экспрессируются в незрелом виде — в виде преламинов. Для созревания им необходимо пройти множественные посттрансляционные модификации карбокситерминального CAAX-мотива (где С – это цистеин, А – алифатическая аминокислота, Х – любая другая аминокислота). В ходе них с помощью металлопротеиназы Zmpste24 от преламинина А удаляются 15 аминокислот.45

Мутации генах, Lmna и Zmpste24 ответственны за несколько прогероидных синдромов человека, объединенных общим названием “прогероидные ламинопатии”. Это, например, синдром Хатчинсона-Гилфорда, атипичный синдром Вернера, рестриктивная дермопатия и мандибулоакральная дисплазия. Сегодня нам известно, что изменения ядерной оболочки происходят и при обычном старении.46

Мыши без Zmpste24 и Lmna используются в исследованиях синдрома Хатчинсона-Гилфорда, поскольку у них повторяется большинство прогероидных проявлений, присутствующих у пациентов с этой прогерией. Используя эти животные модели, знаменитая команда К. Лопес-Отин, первой описавшая классические девять признаков старения, обнаружила,47 что активация NF-κB — связующее звено между дефектами ядерной пластинки, системным воспалением и прогероидными фенотипами. При этом генетическая или фармакологическая блокада NF-κB значительно увеличивала продолжительность жизни мышей с нокаутом Zmpste24 и Lmna.48 49

Важные исследования были проведены на мышах с нокаутом одной из субъединиц NF-κB — Nfkb1. О ней мы уже упоминали ранее в связи с её противовоспалительными эффектами. У мышей без Nfkb1 происходила гиперактивация провоспалительного димера NF-κB, усиливалось системное воспаление, уровень окислительного стресса и укорачивались теломеры. У них развивались алопеция, скелетные аномалии, Это еще раз доказывается ведущую роль NF-κB в процессе старения. Кроме прогероидных и мутантных моделей животных, блокада NF-κB увеличивала продолжительность жизни и у обычных дрозофил.50 51 52 32

В ряде исследований показано, что NF-κB активируется при старении через известные сигнальных путей инсулина/инсулиноподобного фактора, mTOR и ренин-ангиотензин-альдостероновой системы (РААС). В то же время ограничение калорий, метформин, ресвератрол и рапамицин оказывают свои полезные эффекты, подавляя, кроме прочего, активность NF-κB.

В работе 2021 года команда известного геронтолога Нира Барзилая показала взаимосвязь сигнальных путей NF-kB и протеинкиназы С (РКС) с долголетием у людей. Они провели анализ 700 генов, потенциально связанных со старением, используя данные 450 долгожителей. Ученые определили три гена, оказывающие наибольшее влияние на долголетие у людей. Это гены кластерина CLU (который снижает риск болезни Альцгеймера и подавляет активность NF-kB), ингибитора NF-kB NFKBIA и одной из протеинкиназ С, PRKCH. Как пишут авторы, варианты этих генов у долгожителей подавляли активность сигнальных путей NF-kB и РКС. Причем для всех этих генов по отдельности ранее была показана взаимосвязь со старением и на животных моделях. Наконец, тоже самое было подтверждено на большой выборке долгожителей.53 54 35 55

Our results indicate that reduced PKC and NF-kB signaling activity may promote longevity in humans, as observed in model organisms. Further research will eventually unravel the new role of PKC and NF-κB signaling in lifespan and cognitive function in humans and provide important insights into the molecular underpinnings of aging56.

Association of NF-κB with epigenetic mechanisms of aging

It is well known that epigenetic changes occur in living organisms with age. Because of them, some genes that should be “silent” are activated. Others, on the contrary, are suppressed, reducing their normal activity. Such epigenetic changes, associated in particular with DNA base methylation and histone modification, are one of the nine classic signs of aging29. In light of our knowledge of NF-κB, it would be surprising if its age-related activation was not associated with certain changes in the epigenome. And indeed it is.

In particular, this was shown in their recent work by Elizabeth Binder and her colleagues. The main object of their study was the chaperone protein FKBP5. It increases its activity in response to various stresses and modulates the body’s stress response. It was previously described that FKBP5 activation was observed not only under stress and stimulation with glucocorticoids, but also during aging. In particular, this occurs in the aging brain, where FKBP5 promotes tau-related neurodegenerative processes. Using large data arrays obtained in human studies, E. Binder and colleagues found that with aging, there is a decrease in the level of methylation of cytosine-guanine dinucleotides (CpG) in the FKBP5 gene, due to which its expression level increases. At the same time, it became known that stress received at an early age accelerates the process of FKBP5 demethylation57.

Remarkably, one of the underlying targets of active FKBP5 is NF-κB. Its activity also increases, enhancing inflammatory processes. Since FKBP5 is involved in building scaffolds of regulatory protein complexes, it can enhance NF-κB signaling by influencing protein-protein interactions between regulators of the NF-κB pathway. The authors note that MAP3K14 and CHUK, the transcript pair most affected by elevated FKBP5 levels, encode two key regulatory kinases of the NF-kB signaling pathway, NIK and IKKα. The scientists determined that upregulation of FKBP5 activity enhances the binding and formation of the NIK-IKKα complex. This leads to subsequent activation of NF-kB. But that’s not all. Researchers in the course of analyzing all these processes found the formation of a positive feedback loop: NF-kV, chaperone-activated FKBP5, in turn, stimulated an increase in the level of its activator. This is another mechanism for the formation of long-term chronic inflammation. Finally, the researchers found that stress and aging-induced declines in FKBP5 methylation are associated with an increased risk of myocardial infarction in humans57.

In 2017, American neuroscientists David Bennett and colleagues identified another epigenetic mechanism for the age-dependent increase in NF-κB activity in the human and mouse brains. In the first step, using 79 samples of human brain tissue, they identified genes whose expression increased or decreased with aging.
Scientists have found that among the genes that are activated during aging, most are associated with inflammation. Analysis of epigenomic changes showed that all these genes with increased age-related expression had a characteristic feature associated with one of the epigenetic modifications of H3K27 histones, acetylation. The authors determined that these age-related histone epigenomic changes increased the activity of pro-inflammatory genes in the human and mouse brains. Including the components of the NF-κB signaling pathway58.

Also, several studies have described how age-related epigenetic drift causes an increase in the levels of pro-inflammatory cytokines and chemokines, TNF-α, IL-23 and CXCL10, in animals and humans. This is due to the fact that during aging there is a loss of methylation of CpG dinucleotides in the promoter of their genes and demethylation of histone lysine. This leads to an increase in their expression and increased inflammation. This also involves NF-κB, which is activated by pro-inflammatory cytokines. In the case of age-related increased activity of CXCL1059, scientists additionally recorded a decrease in cognitive functions, an increase in neurodegenerative processes, and an increased risk of developing Alzheimer’s disease. This again shows the role of inflammation in age-related degeneration60 61 62.

In two independent animal studies, A. Simon and A. Amer and their colleagues demonstrated another epigenetic mechanism for the age-related increase in inflammation. This time it turned out to be connected, as it may not seem surprising at first glance, with autophagy (a separate story about autophagy, NF-κB and aging is yet to come). Autophagy, epigenetics, and age-related inflammation? Yes exactly. Scientists have found that with aging, a number of epigenetic changes occur, leading to a deterioration in autophagy function. This is due to an increase in the activity of one of the DNA methyltransferases, DNMT2 (which catalyzes DNA methylation). And, as a result, with methylation (and suppression of expression) of the promoter regions of two autophagy genes, Atg5 and LC3B. Methylation of CpG islands in the promoter region, as we know, suppresses the expression of the corresponding genes due to the fact that transcription factors recognize these promoters worse. Without normal autophagy, old rodent macrophages functioned significantly worse, a metabolic shift towards glycolysis and a pro-inflammatory phenotype with increased secretion of pro-inflammatory cytokines were observed. Which, as we remember, act as activators of NF-κB63 64.

Extracellular DNA (ecDNA) has also been implicated in these processes. Normally, DNA should be located in the nucleus of the cell. However, DNA fragments can be found outside the nucleus, for example, during cell damage and apoptosis. With aging, the number of cfDNA fragments increases along with a decrease in its methylation level. Such low-methylated pieces of DNA, similar to microbial ones, are perceived by the immune system as the DNA of pathogens. As a result, an immune inflammatory response is triggered. In a similar way, it stimulates age-related inflammation and retrotransposon L-1, penetrating into the cytoplasm of old cells65 66 67 68.

As we have already noted, inflammatory processes with the participation of NF-κB are characterized by the formation of “vicious cycles” – positive feedback loops. For example, in the case of increased ROS production and oxidative stress during aging. They activate NF-κB, which in turn stimulates even more oxidative stress. As it turns out, vicious cycles can also be found in the age-related epigenetic drift associated with NF-κB signaling and inflammation. So, for example, one of the pro-inflammatory cytokines, IL-6, contributes to a decrease in methylation and an increase in the activity of the above-mentioned transposon L-1. At the same time, IL-6 also stimulated the reverse process — increased methylation and suppression of the expression of tumor suppressor genes, CHFR, GATA5, and PAX669 70 71 72.

Another mechanism for the effect of inflammation on the epigenome is via KDM6B demethylase, which removes repressive epigenetic marks on the histones H3K27me2 and H3K27me3. This intensifies the processes of inflammation and cellular aging. The expression of KDM6B is increased as a result of the activity of the NF-kB signaling pathway.

How does NF-kB suppress the body's ability to recover?

In the cells of living organisms, products are constantly formed that have served their time or, for various reasons, are “spoiled”. For example, oxidized ROS. Such cellular structures (proteins and even entire organelles such as mitochondria) that have lost their normal function must be removed from the cell. After that, new, normally functioning structures take their place. This process is ongoing. It is carried out with the help of autophagy. Let’s describe this process. The structure to be removed is surrounded by a membrane, forming an autophagosome, and moves to the lysosome, which contains special enzymes for the degradation of damaged structures. Some of the components of these structures are recycled – they are used either to build cell components or to produce energy, for example, during starvation. Autophagy also destroys invading pathogens, bacteria and viruses. There are several types of autophagy (macro- and microautophagy, chaperone-mediated autophagy, selective autophagy).

It is now known that autophagy activity decreases with aging. This is due to the accumulation of damaged cellular structures, the progression of the development of senile phenotypes and age-related pathologies. For example, neurodegeneration. Age-related autophagy suppression in the hypothalamus followed by NF-κB activation has been associated with metabolic disorders, obesity, and diabetes. Characteristically, the AMPK and SIRT signaling pathways (whose activity declines with aging) activate autophagy and downregulate the activity of the NF-κB signaling pathway and inflammation73 74 75.

Inflammatory processes also depend on normal autophagy. A decrease in its function leads to an increase in inflammation and an increase in the activity of the NF-κB signaling pathway. Also, defective autophagy can increase inflammation in two more ways: by activating the assembly of a pro-inflammatory protein complex, the inflammasome, and by disrupting the normal cleaning of tissues from apoptotic bodies (remnants of cell death). Inflammasomes, in turn, can block the process of autophagy. Here again we see a vicious circle: the deterioration of autophagy function stimulates the activity of inflammasomes, which will further suppress normal autophagy76 77 78 79 80 81.

Notably, in some cases, NF-κB can stimulate autophagy. For example, in the case of heat shock: NF-κB signaling triggers autophagy during the recovery period from heat shock and thus maintains cell survival. Inhibition of NF-kB activation blocks the autophagic response and enhances cell death after heat shock. In these processes, NF-κB increases the level of expression of BAG3-HspB8 complexes, and this, in turn, enhances autophagy and clearance of irreversibly damaged proteins82. The reverse process is also observed, when NF-kB suppresses autophagy. This happens through the activation of the NF-kB signaling pathways of mTOR and insulin/IGF and some other autophagy inhibitory proteins, as well as the activation of the production of ROS and nitric oxide83.

Thus, NF-kB can both suppress and stimulate autophagy by controlling the expression of several well-known autophagy activators and inhibitors. This is what happens in a young and healthy organism, where signaling pathways dynamically interact with each other under various stressful conditions.

With aging, the normal autophagy-NF-kB interaction is disrupted and a decrease in autophagy function contributes to the activation of the NF-kB signaling pathway. And NF-kB, together with the inflammasome and other signaling pathways (such as mTOR), suppresses autophagy. Due to this, a positive feedback loop is formed, which enhances age-related inflammation and aging in general83 84 85 86.

How can self-DNA activate aging mechanisms through NF-κB?

The DNA in a cell is housed in the nucleus and mitochondria and is separated from the rest of the cell. According to the well-known evolutionary biologist Yevgeny Kunin in his book The Logic of Chance, such a division arose as a result of the invasion of the mobile elements of a symbiotic bacterium into the cell, which later became a mitochondrion. This allows strictly controlled processes in the nucleus associated with gene expression and repair of damaged DNA, as well as spatial separation of transcription and translation. In order to protect themselves from invading parasites, organisms have evolved immune responses to foreign DNA, which is detected by special sensors outside the nucleus and mitochondria. However, in addition to foreign DNA, sometimes its own, endogenous cytoplasmic DNA (cDNA) also enters the cytosol of the cell87.

In total, four types of endogenous cDNA are distinguished:

  • microkernels;
  • cytoplasmic fragments;
  • chromatin;
  • mitochondrial DNA

Micronuclei are fragments of chromosomes resulting from mitotic defects (that is, during cell division). They are initially surrounded by a nuclear envelope that separates them from the cytoplasm. However, this shell is fragile and quickly breaks. DNA from micronuclei that has entered the cytosol of a cell is perceived by the immune system as a danger signal. As a result, an inflammatory response is triggered. Today it is known that the formation of micronuclei is associated with oncogenesis. The scientists also propose to use micronuclei as a biomarker of genomic instability88 89.

An increase in the content of cells with micronuclei in the body leads to accelerated aging, the development of oncology and neurodegenerative diseases. In addition, studies have shown that an increase in the number of micronuclei is associated with senile asthenia90 91 92.

Cytoplasmic chromatin fragments

Cytoplasmic chromatin fragments (CPCs) are another type of endogenous cDNA. Their role in the development of cellular senescence has been described only recently. It is known that senescent cells displace chromatin fragments (normally all localized in the nucleus) from the nucleus into the cytoplasm. These CPCs then induce SASP production in old cells. Senescent cells secrete factors (inflammatory cytokines, immunomodulators, growth factors, proteases) that increase inflammation and cellular aging of neighboring cells, causing a “bystander effect”93

A study by P. Adams and colleagues conducted in 2020 showed that mitochondrial dysfunction also plays a role in these processes. It was found that the formation of CPC and the subsequent activation of SASP are triggered by mitochondrial-nuclear retrograde signaling pathways. The key role, according to scientists, is played by an increase in the level of ROS production in dysfunctional mitochondria, the number of which increases with aging. CPCs are recognized by the cytosolic DNA sensor cGAS, which leads to the activation of the STING protein. In turn, the cGAS-STING signaling pathway activates NF-κB and leads to the transcription of pro-inflammatory cytokine genes. All this contributes to the formation and maintenance of age-related inflammation94.

Mitochondrial DNA

Mitochondrial DNA (mtDNA) is another source of endogenous cDNA in cells. It enters the cytosol of the cell from dysfunctional mitochondria formed as a result of oxidative stress and due to damage to the mitochondrial membrane. When mtDNA enters the cytosol, it is perceived by the immune system as a danger signal, the cGAS-STING signaling pathway is triggered, and NF-κB is activated. Viral and bacterial infections also lead to the release of mtDNA into the cytosol of the cell, part of the body’s defense system. Cell death due to apoptosis is also associated with the entry of mtDNA into the cytosol. It is known that cytosolic mtDNA activates the NLRP3 inflammasome. Notably, melatonin suppresses cytosolic mtDNA-induced neuroinflammatory signaling during accelerated aging and neurodegeneration95 96.


Finally, the fourth source of cytosolic endogenous DNA is transposons. In 2019, the team of Vera Gorbunova and colleagues from the University of Rochester showed that retrotransposons are activated during aging. After that, their DNA enters the cytosol and triggers an interferon response that stimulates age-related inflammation and the formation of SASP in old cells97.

How can SASP be associated with NF-κB? Research shows this relationship is bidirectional. First, the NF-κB signaling pathway stimulates the development of SASP by its activity. Then the reverse action can take place. As shown by a recent study by British gerontologists from Queen Mary University, old cells can activate the NF-κB signaling pathway. This is due to the very same SASPs packaged in extracellular vesicles that are secreted by old cells. For the umpteenth time here we can observe the formation of another vicious cycle involving NF-κB98 99.

NF-κB disrupts the body's circadian rhythms

The term “circadian rhythms” today is used to denote endogenous (internal) changes in biological processes in the body with coverage in a 24-hour period. They are associated with the daily rotation of the Earth and the night/day (light/dark) cycle. Such endogenous rhythms have been described in almost all living organisms, from photosynthetic prokaryotes to higher eukaryotes, including humans. They are involved in the regulation of physiological processes to adapt the internal environment to changing external signals. At the molecular level, the circadian clock consists of multiple sets of transcription factors and autoregulatory transcription-translation feedback loops100 101.

Remarkably, in addition to their primary role as a generator of the circadian rhythm, these transcription factors, as the researchers found, also play a key role in controlling the physiological functions of virtually all tissues and organs. They regulate several processes, including cell proliferation, response to DNA damage and repair, angiogenesis, metabolic and redox homeostasis. And also – the inflammatory-immune response and processes associated with aging. Both genetic and environmental disturbances in circadian rhythms have been shown in animal and human studies to be associated with accelerated aging and reduced life expectancy. It is estimated that a significant proportion (up to 20%) of the genes expressed in any particular cell or tissue undergo circadian fluctuations at the mRNA level102 103 104 105.

In 2022, several new major works have been published on the relationship between circadian rhythms and aging. Thus, a team of biologists from the University of Rochester described circadian and pluripotent gene networks associated with the regulation of age-related processes. Thus, it describes a number of “circadian” genes (CLOCK, BMAL1, NPAS2, PER1, PER2, CRY1, CRY2), the products of which, in turn, regulate the expression of many genes associated with aging (with the perception of nutrients, DNA repair, inflammation and immunity, RNA export, nucleotide metabolism, etc.)106.

In another work, P. Kapahi and colleagues described how aging of the Drosophila eye and a decrease in the function of circadian rhythm genes are associated with systemic inflammation and aging. However, calorie restriction mitigated these negative effects. As the authors write, it is possible that the relationship between eye aging and dysfunction of circadian rhythms with aging can explain the longevity of animals that live mostly in darkness. For example, in bats or naked mole rats: “We report that disruption of CLK function in photoreceptors accelerates vision decline and shortens lifespan, while wild-type CLK overexpression protects against age-related vision loss and reverses high-calorie diet-dependent decline in photoreceptor function. Our data also shows that photoreceptor stress (with prolonged light exposure) has a detrimental effect on the health of the body: excessive stimulation of photoreceptors induced a systemic immune response and reduced life expectancy. Our results also support the notion that age-related deterioration of the visual system is costly for body physiology. This may explain why some cave-dwelling animals whose visual systems have undergone regressive evolution (such as cave-dwelling fish and naked mole rats) live particularly long lives. Failure to develop the visual system may act as a survival mechanism, allowing organisms to avoid the damage and inflammation caused by age-related retinal degeneration. Ultimately, the development of the visual system, which is critical for reproduction and survival, can harm the body later in life. Thus, vision may be an example of an antagonistically pleiotropic mechanism that determines lifespan107.

In two more studies in 2021 and 2022, the team of renowned gerontologist J. Belmonte described several previously unknown aspects related to circadian regulators.

They determined the non-canonical function of these regulators, namely the maintenance of the structure and configuration of dense chromatin (heterochromatin), which is important for normal gene expression. As we know, the amount of heterochromatin decreases with aging. The circadian genes, CLOCK and BMAL1, maintained the “young” architecture of heterochromatin and the normal function of stem cells, preventing their aging.

It is noteworthy that a similar action has recently been described for sirtuin proteins, known for their important role in the fight against aging. Thus, sirtuins SIRT3 and SIRT7 stabilize heterochromatin and counteract the aging of stem cells. In all cases, the favorable effect of circadian regulators and sirtuins on stem cells was associated with the suppression of the activity of L-1 transposons. They, as we know, are activated during aging and contribute to the instability of the genome, the processes of cellular aging and inflammation108 109 110 111.

We now know for sure that circadian rhythms are essential for good health and longevity, and that their function is closely related to inflammation. But how exactly do circadian genes interact with the NF-κB signaling pathway?

Studies have shown that the activity of the NF-κB signaling pathway disrupts the regulation of circadian rhythms. Thus, it can act as a repressor of the transcriptional activity of the main circadian complex BMAL1/CLOCK. At the same time, NF-κB binds to the transactivation domain of BMAL1, like the main repressor of the circadian signaling pathway, CRY1. Remarkably, in a healthy young body, under normal conditions of immune and inflammatory homeostasis, basal NF-κB activity contributes to circadian homeostasis. In turn, one of the main circadian genes, CLOCK, stimulates an increase in NF-κB expression by forming a complex with one of the NF-κB subunits, p65. Another circadian rhythm gene, BMAL1, reduces NF-κB activity. The main repressor of circadian signaling activity, CRY, also contributes to the reduction of NF-κB activity.

This delicate regulatory interplay between inflammatory and circadian signaling pathways is disrupted with aging. When the NF-κB signaling becomes overactive, circadian rhythms fail. As a result, both signaling pathways begin to reinforce each other’s dysfunction. As a consequence, there is a disruption in the normal function of numerous signaling pathways regulated by genes for circadian rhythms and NF-κB, and an increase in aging processes112 113 114.

NF-κB as a factor in the development of age-related diseases

Cardiovascular diseases

NF-κB activity is associated with vascular aging and atherosclerosis. Monocytes are believed to play a key role in atherosclerosis. Which are recruited into the intima of the arteries and turn into macrophages, which then absorb LDL and form plaques. It is already known that NF-κB regulates the expression of a large number of genes involved in the pathogenesis of atherosclerosis. In vascular endothelial cells, NF-κB stimulates the production of pro-inflammatory cytokines, chemotactic factors, and adhesion molecules. This promotes monocyte recruitment and disease progression. An important role in the activation of NF-κB in atherosclerosis is played by the shear stress of the vessel wall (that is, the stress caused by blood flow). In atherogenesis, it has the character of an oscillatory or oscillatory (oscillatory shear stresses), especially in places of bends and bifurcation of blood vessels. This contributes to the development of pro-inflammatory and pro-oxidative processes, incl. and activation of the NF-κB pathway. In experiments on an animal model of atherosclerosis, suppression of NF-κB activity protected mice from the development of atherosclerosis115 116 117 118.

The relationship of the NF-κB signaling pathway with the functioning of advanced glycation end products (AGEs) and aging of the extracellular matrix of arteries has also been described. It is well known that AGEs, via the RAGE receptor, trigger several cellular programs, including the NF-kB signaling pathway, which increases inflammation. In addition, the AGE-RAGE complex, through the activation of NF-κB, enhances the expression of collagen Ia1 and Ia2 in the arteries. The AGE-RAGE signaling pathway induces RelA (NF-κB subunit) phosphorylation at three specific residues, T254, S311 and S536. These modifications are necessary for the transcription of collagen I genes. An increase in collagen content is a hallmark of arterial aging. This study showed a potential mechanistic link between RAGE signaling, NF-κB activation, and aging-associated changes in arterial structure and function119.

Above, we have already reported on animal experiments with knockout of the anti-inflammatory subunit NF-κB, NFKB1. Genetic variants (polymorphisms) leading to decreased NFKB1 function have also been described in humans. Back in 2004, the first NFKB1 polymorphism was discovered, due to which the expression of this gene is reduced and the risk of developing ulcerative colitis increases. Later, the relationship of NFKB1 polymorphisms with a decrease in its activity in people with other diseases, in particular, with an increased risk of developing heart disease (heart failure, coronary heart disease, myocardial infarction), was described120 121.

Diseases of the musculoskeletal system

Age-related musculoskeletal disorders, including osteoporosis and osteoarthritis, may also be associated with NF-κB activation through mechanical stress. Thus, the impact of excessive mechanical stress on the articular cartilage causes the pathogenesis of osteoarthritis. These pathological processes are realized through the Gremlin-1 protein, which is activated by mechanical stress in chondrocytes. In turn, it itself activates the NF-κB signaling pathway, increasing inflammation and other destructive processes122.

Neurodegenerative diseases

Alzheimer’s disease (AD) is the most common cause of age-related dementia, characterized by the formation of fibrillar tangles and β-amyloid plaques. Although the causes of AD remain poorly understood, one common characteristic of all patients is an increased level of chronic inflammation. In the brain of AD patients, NF-κB-regulated cytokines IL-1β and TNFα are abundant. Studies in mice have highlighted the potential role of IL-6 and IL-1β in the development of AD. Animals injected into the brain with IL-1α or β had increased plaque formation characteristic of AD123 124.

A possible mechanism for the increase in cytokine levels observed in AD is the result of stimulation of Aβ activity by NF-kB in microglia. Suppression of NF-κB activity in microglia leads to a decrease in neurotoxicity. It is known that the APP amyloid precursor protein gene contains sequences to which NF-κB specifically binds. This enhances the expression of APP. This, in turn, may be associated with increased beta-amyloid accumulation and neurodegeneration125.

The role of inflammation and NF-κB activation in the development of AD is further supported by studies in animal models. It has been shown that injections of the bacterial component, lipopolysaccharide (LPS), accelerate the progression of AD. At the same time, as we know, chronic viral infections and associated inflammation also act as a risk factor for the development of AD and cognitive decline. We also know about the activation of retroelements in neurodegeneration. This is also associated with the development of inflammation and increased activity of NF-κB126.
Taken together, these data suggest that NF-κB plays an important role in plaque formation and the progression of Alzheimer’s disease.

There are also a number of age-related pathologies that are formed with the participation of the NF-κB signaling pathway and due to the development of inflammation. These are Parkinson’s disease and amyotrophic lateral sclerosis, metabolic disorders (obesity, insulin resistance and type 2 diabetes), sarcopenia and eye diseases127 128 129 130.

Summing up

Summing up, we will cite the statement of one famous scientist, microbiologist Rajan Sen, a colleague of D. Baltimore and his co-author in the work, during which NF-κB was first discovered. He also emphasizes the extraordinary complexity and versatility of this factor’s involvement in biological processes and draws attention to what remains to be learned about it in the future:

Given the extensive knowledge base of NF-kB, it is worth considering the future direction of its research. One aspect of the biology of NF-kB that is not well understood is how it regulates complex patterns of gene expression. In general, the problem is that NF-kB is induced by various stimuli in almost all cell and tissue types studied so far. But the pattern of gene expression is usually specific to the stimulus and cell type. Understanding the basis for the selectivity of NF-kB-dependent gene expression could greatly facilitate the development of therapeutic agents aimed at limiting NF-kB function. For example, it will be possible to modulate NF-kB-dependent gene expression in some tissues, but not change it in others. Or selectively affect some NF-kB target genes. Among other things, such studies will alleviate the main problem of side effects and prompt the development of a broad spectrum of anti-NF-kB therapies. Determining the mechanisms regulating tissue- and stimulus-specific NF-kB responses is likely to be a central issue in his research for years to come131.

Alexey Rzheshevsky

Alexey Rzheshevsky

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