Aging involves persistent dysregulation of nutrient sensing, energy metabolism, protein homeostasis, and chronic inflammation. IIS, mTOR, AMPK, NF-κB, and Sirtuins are interconnected through nodes including AKT, FOXO, ULK1, and NAD⁺ and jointly regulate cell growth, autophagy, stress adaptation, and the senescence-associated secretory phenotype.

Keywords: aging; IIS; IGF-1; mTOR; AMPK; NF-κB; Sirtuins; NAD⁺; autophagy; senescence-associated secretory phenotype

1 Functional Basis of Aging-Related Signaling Networks

1.1 Nutrient Sensing and Energy Homeostasis

Cells sense insulin, growth factors, amino acids, and nutrient availability through IIS and mTOR and monitor metabolic states such as ATP, AMP, and NAD⁺ through AMPK and Sirtuins. Under nutrient-rich conditions, IIS and mTORC1 promote the synthesis of proteins, lipids, and nucleotides; under energy-deficient conditions, AMPK suppresses anabolic metabolism and promotes fatty acid oxidation, autophagy, and mitochondrial quality control. During aging, the balance among these pathways changes, reducing cellular adaptability to nutrient excess, energy stress, and damaging stimuli.

1.2 Inflammation and Cellular Homeostasis

DNA damage, mitochondrial dysfunction, oxidative stress, and the accumulation of senescent cells can persistently activate inflammatory pathways such as NF-κB and promote the production of IL-6, IL-8, and other components of the senescence-associated secretory phenotype. At the same time, reduced autophagic and protein quality-control capacity increases the accumulation of abnormal proteins and damaged organelles, further intensifying cellular stress and inflammatory responses. Therefore, the central change in aging-related signaling networks is not simply enhancement or suppression of a single pathway but loss of coordination among growth, metabolism, clearance, and inflammatory regulation.

Table 1 Major Aging-Related Signaling Pathways and Their Functions

2 IIS-AKT-FOXO Signaling and Aging

2.1 Activation of IIS Signaling

After insulin or IGF-1 binds its corresponding receptor, phosphorylation of insulin receptor substrate proteins and activation of PI3K-AKT signaling are promoted. AKT further phosphorylates FOXO transcription factors and induces their translocation from the nucleus to the cytoplasm, thereby reducing FOXO-mediated expression of genes involved in antioxidant defense, stress resistance, autophagy, and metabolic adaptation. AKT can also promote mTORC1 activation by inhibiting the TSC1/TSC2 complex, thereby connecting growth-factor signaling with nutrient sensing and protein synthesis.

2.2 Reduced IIS and Lifespan Regulation

Reduced IIS signaling can enhance FOXO activity in multiple model organisms and is associated with antioxidant defense, protein homeostasis, and lifespan extension. In mammals, the GH-IGF-1 axis also participates in growth, bone metabolism, muscle maintenance, and tissue repair, so lower activity is not necessarily always beneficial. Long-term or systemic inhibition may impair tissue function, and studies need to distinguish developmental from adult-stage effects and systemic from tissue-specific effects.

2.3 Crosstalk Between IIS and Other Signaling Pathways

IIS can activate mTORC1 through AKT, whereas the mTORC1 downstream effector S6K can negatively regulate IRS proteins, forming a feedback-inhibition loop. Enhanced IIS may also reduce FOXO- and AMPK-associated stress-adaptation capacity. The effects of IIS on aging arise not only from growth signaling itself but also from its integrated regulation of mTOR, autophagy, energy metabolism, and oxidative stress.

3 mTOR Signaling and the Regulation of Autophagy, Protein Synthesis, and SASP

3.1 Regulation of Anabolic Metabolism and Autophagy by mTORC1

mTOR mainly forms two complexes, mTORC1 and mTORC2, with aging research focusing primarily on mTORC1. mTORC1 promotes protein translation through S6K and 4E-BP1 and supports lipid and nucleotide synthesis; it can also phosphorylate ULK1 and suppress autophagy initiation. Persistent nutrient abundance or excessive mTORC1 activation can reduce the efficiency of damaged protein and organelle clearance, thereby impairing protein homeostasis and stress resistance.

3.2 Regulation of SASP by mTORC1

Senescent cells can produce various inflammatory factors, growth factors, and extracellular matrix-regulating proteins, forming the senescence-associated secretory phenotype. mTORC1 can regulate the translation of proteins such as IL-1α and MAPKAPK2 and indirectly enhance NF-κB-associated transcription. Inhibition of mTORC1 can reduce certain SASP components, but SASP profiles generated by different cell types and senescence-inducing methods are not identical, and a decrease in a single inflammatory factor cannot be used alone to conclude that cellular senescence has been reversed.

3.3 Research Boundaries of mTOR Inhibition

Rapamycin inhibits mTORC1 by binding FKBP12 and is an important tool for studying nutrient sensing, autophagy, and lifespan regulation. Long-term treatment may also affect mTORC2 in certain cells and tissues and produce immune, metabolic, and tissue-repair effects. Therefore, mTOR intervention studies need to distinguish acute from long-term treatment and evaluate mTORC1 downstream phosphorylation, autophagic flux, and cellular function.

4 AMPK Signaling and Adaptation to Energy Stress

4.1 Energy-Sensing Function of AMPK

Decreased ATP and relative increases in AMP or ADP can promote AMPK activation. Activated AMPK suppresses energy-intensive synthetic processes involving fatty acids, cholesterol, proteins, and other molecules while promoting glucose uptake, fatty acid oxidation, and energy restoration. In some aged tissues, reduced AMPK responsiveness to metabolic stress may weaken the capacity of cells to restore energy homeostasis under nutrient deprivation, exercise, or mitochondrial stress.

4.2 Regulation of mTOR and Autophagy by AMPK

AMPK can inhibit mTORC1 by phosphorylating TSC2 and Raptor and can directly regulate ULK1 to promote autophagy initiation. This effect helps reduce anabolic metabolism during energy deficiency and facilitates the clearance of damaged mitochondria and abnormal proteins. To determine whether AMPK truly enhances autophagy, LC3 conversion, p62 degradation, and autophagic flux under lysosomal inhibition should be measured; increased LC3-II alone is insufficient to support this conclusion.

4.3 AMPK, Sirtuins, and Inflammatory Signaling

AMPK can enhance SIRT1-associated responses by affecting NAD⁺ metabolism, while SIRT1 can influence AMPK and mitochondrial function by regulating proteins such as LKB1, PGC-1α, and FOXO. AMPK can also indirectly suppress NF-κB-associated inflammatory signaling. Metabolic regulators such as Metformin can alter mitochondrial energy metabolism and activate AMPK under certain conditions, but their actions include both AMPK-dependent and AMPK-independent mechanisms, and all effects should not be attributed to a single pathway.

5 NF-κB Signaling and Inflammatory Aging

5.1 NF-κB Activation and Inflammatory Responses

Inflammatory factors, pathogen-associated molecules, oxidative stress, and DNA damage can activate the IKK complex, promote IκB degradation, and allow NF-κB to enter the nucleus and induce inflammatory gene expression. Persistent low-level NF-κB activation in aged tissues is associated with chronic inflammation, immune dysfunction, and alterations in the tissue microenvironment, while SASP produced by senescent cells can further activate NF-κB signaling in surrounding cells.

5.2 NF-κB and Maintenance of SASP

NF-κB is an important transcriptional regulator of multiple SASP factors. DNA damage responses, p38 MAPK, mTORC1, cytosolic nucleic acid sensing, and other signals can converge on the NF-κB network and cause senescent cells to continuously release inflammatory mediators. When evaluating NF-κB-associated SASP, cellular senescence markers, cell number, and cell death should also be assessed to avoid misinterpreting factor reduction caused by cytotoxicity as specific inhibition of SASP.

5.3 Limitations of NF-κB Intervention

NF-κB also participates in anti-infective defense, immune-cell activation, and tissue repair, and sustained systemic inhibition may impair normal defense functions. Compared with complete blockade of NF-κB, regulation of specific upstream stimuli, tissue sources, or SASP branches is more conducive to distinguishing pathological chronic inflammation from normal immune responses.

6 Sirtuins and NAD⁺ Metabolism

6.1 Age-Related Changes in NAD⁺

NAD⁺ participates not only in redox reactions but also serves as a substrate for enzymes such as Sirtuins and PARP. With increasing age, NAD⁺ biosynthetic capacity declines in some tissues, whereas DNA damage, inflammation, and increased activity of NAD-consuming enzymes such as CD38 can accelerate NAD⁺ depletion. Aging-associated inflammation may also promote CD38 expression in immune cells and further affect local NAD⁺ levels and Sirtuin activity.

NAD⁺ precursors such as Nicotinamide Riboside and Nicotinamide Mononucleotide can increase NAD⁺ levels in some tissues or experimental systems, but an increase in NAD⁺ does not necessarily equal lifespan extension or improvement of all aging phenotypes. Evaluation of such interventions requires distinction among changes in metabolite levels, improvements in tissue function, and long-term health outcomes.

6.2 Major Regulatory Roles of SIRT1

SIRT1 is an NAD⁺-dependent deacetylase that regulates proteins including FOXO, PGC-1α, p53, and NF-κB. Through these substrates, SIRT1 participates in the regulation of mitochondrial biogenesis, oxidative stress, autophagy, inflammation, and cell survival. SIRT1 can deacetylate NF-κB RelA/p65 and reduce the expression of certain inflammatory genes and can also form metabolic regulatory feedback with AMPK.

6.3 SIRT6 and Chromatin Homeostasis

SIRT6 is mainly localized in the nucleus and participates in chromatin regulation, DNA repair, telomere stability, and metabolic gene expression. SIRT6 deficiency can cause genomic instability and multiple premature aging-like changes, although its effects are not identical among different cell types. SIRT6-related research needs to consider enzymatic activity, substrate specificity, and tissue dependence simultaneously.

6.4 Evaluation of Sirtuin Modulators

Resveratrol can affect AMPK, Nrf2, inflammatory, and mitochondrial signaling, but it has multiple targets, and all experimental results cannot be simply interpreted as SIRT1 activation. When investigating Sirtuin dependence, knockdown or knockout of SIRT1 or other family members, inhibitor controls, and enzyme-activity measurements should be combined to distinguish direct effects from secondary metabolic effects.

7 Potential of Different Pathways in Anti-Aging Research

7.1 mTORC1 as an Intervention Node With Relatively Comprehensive Evidence

From yeast, nematodes, and fruit flies to mammalian models, reduced mTORC1 activity has substantial research support for associations with lifespan extension, improved protein homeostasis, and attenuation of certain age-related phenotypes. mTORC1 connects nutrient sensing, protein synthesis, autophagy, and SASP and is therefore a major intervention node in aging research. However, the immunometabolic effects and long-term safety window of mTOR inhibition still need to be evaluated in specific models.

7.2 The AMPK-Sirtuin-NAD⁺ Axis Emphasizes Metabolic Adaptation

AMPK, Sirtuins, and NAD⁺ metabolism mainly affect cellular adaptability to energy stress, exercise, oxidative stress, and mitochondrial damage. This network is suitable for investigating metabolic health and healthspan, but related compounds generally have multitarget effects, and long-term benefits in humans cannot be inferred solely from animal lifespan studies or short-term metabolic indicators.

7.3 IIS and NF-κB Require Tissue-Specific Regulation

Reducing IIS can enhance FOXO activity and stress resistance, but excessive inhibition may impair growth, muscle maintenance, and tissue repair. Inhibiting NF-κB can reduce chronic inflammation and SASP but may also weaken immune defense. Therefore, these pathways are more suitable for intervention under conditions in which the target tissue, disease stage, and source of inflammation are clearly defined rather than through sustained systemic blockade.

8 Compounds for Aging-Related Signaling Pathway Regulation and Metabolic Research

8.1 Products Related to IIS, mTOR, AMPK, and Autophagy Research

8.2 Products Related to NF-κB, Inflammation, and SASP Research

8.3 Products Related to Sirtuin and NAD⁺ Metabolism Research

Aging is jointly driven by nutrient sensing, energy metabolism, protein homeostasis, chronic inflammation, and related processes. Anti-aging signaling research should consider pathway crosstalk, tissue specificity, and intervention timing and should not evaluate intervention effects solely from changes in the expression of a single protein, inflammatory factor, or metabolite.

References

[1] Salminen A, et al. NF-kappaB Signaling in the Aging Process. J Clin Immunol. 2009;29(4):397-405.

[2] Osorio FG, et al. NF-κB Signaling as a Driver of Ageing. Int Rev Cell Mol Biol. 2016;326:133-174.

[3] Chen C, et al. SIRT1 and Aging Related Signaling Pathways. Mech Ageing Dev. 2020;187:111215.

[4] Greer EL, et al. Signaling Networks in Aging. J Cell Sci. 2008;121(Pt 4):407-412.

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