Targeting the Root Causes of Aging

Introduction

Aging is often defined as the progressive deterioration of a person’s physiological integrity over time, leading to diminished physical function. The aging process takes place naturally and uniquely within each person. Although many theories have been developed and studied, none of them have been able to provide a comprehensive account of the aging process [1]. To a greater or lesser extent, the aging process has not been considered an adaptation or a phenomenon with a genetically determined cause. Both the planned aging hypothesis and the damage or error-based aging theory have gained traction in light of recent biological discoveries [2]. According to the first theory,  human cells’ inherent, biologically planned deterioration in structural integrity and capacity to fulfill their intended tasks is inevitable and unavoidable with age. The latter highlights the subtle but cumulative damage inflicted on living organisms, leading to inevitable intrinsic aging [3].

This article will summarize the “hallmarks of aging” previously proposed by López-Otín et al. [4] and Schmauck-Medina et al. [5]. The former proposed nine cellular and molecular hallmarks that contribute to aging, including genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. The latter proposed five new hallmarks of aging: compromised autophagy, microbiome disturbance, altered mechanical properties, splicing dysregulation, and inflammation.

 

These hallmarks should be present throughout the normal aging process, and their experimental aggravation should accelerate the aging process. However, their observed enhancement slows the natural aging process, leading to a long healthy life expectancy.

Hallmarks of Aging

The mechanisms that comprise aging in our bodies are all interrelated in some way. Because of the growth of the field of biological study on aging during the last three decades, several “hallmarks of aging” have emerged. These processes, or “hallmarks,” are the fundamental underlying mechanism of how our bodies age on a cellular level. The following serves as a primer for each of the aforementioned indicators of aging.

1. Stem Cell Exhaustion

Consistent decline in regeneration capacity with age is linked to endogenous stem cell exhaustion, aberrant modifications in the supporting habitats, and functional attrition, all of which occur over time. Therefore, aging may be defined as a process in which tissue-resident stem cells lose their potential to replace damaged cells over time. This highlights the need for more comprehensive evaluations of stem cell aging in an age-dependent setting. Recent advances in the field, such as identifying multiple cell types well defined in lineage development, have aided their characterization in aging [6] and are being used in studying old stem cells.

Numerous stem cells, including muscle [7], hematopoietic [8], and brain stem cells [9], are known to decline with age.

2. Altered Intercellular Communication

The cells in our bodies process an incredible number of signals every day. Many scientists have spent their careers trying to understand the mechanisms of various signals and intercellular channels. In the event of a communication failure, the spread of illness is conceivable. In reality, the great majority of diseases are linked to breakdowns in cellular communication. Alterations in the signals that go between cells, called “altered intercellular communication” in the book “Hallmarks of Aging,” may contribute to the development of some of the diseases and disabilities that are characteristic of old age. Disruptions in intercellular communication are a significant cause of tissue decline with age [1].

One of the most noticeable and significant changes in intercellular signaling due to aging is an increase in continuous inflammatory signaling. Inflammation has a role in almost all age-related chronic diseases, including atherosclerosis, cancer, neurological ailments, and diabetes, to name a few. Altered Intercellular Communication enhance these inflammation signals. This helps explain why scientists believe that elevated inflammatory signals is also a hallmark of aging [10].

3. Genomic Instability

Point mutations, deletions and insertions, chromosomal rearrangements, and whole chromosome numerical alterations are all examples of genomic instability that may cause irreversible changes to the genome’s information content [11]. Genomic instability directly causes cell cycle stress, alterations in gene expression, and alterations in gene regulation. This may provide insight into cellular degeneration and functional decrease as we age. Genomic instability leads to aging, cancer, and other degenerative illnesses.

4. Telomere Attrition

The telomeres are the terminal genetic portions of linear chromosomes. In vertebrates, telomeric DNA is made up of TTAGGG (repetitive DNA sequence), bound together by a collection of proteins that regulate their biological functions and prevent them from mistakenly detected as DNA damage (DDR). An unwarranted DNA damage response is initiated in the case of telomere malfunction [12].

Growing evidence suggests that telomere-specific DNA damage response (tDDR) is crucial in the aging process and the onset of age-related diseases. First, if TAFs (TBP-associated factors) are present in the body, life-extension medicines such as calorie restriction, exercise, rapamycin, and 17-oestradiol could reduce their frequency (telomere-associated DDR foci). A decrease in TAF is seen when senescent cells are eliminated in vivo utilizing senolytic techniques. In contrast, TAFs tend to build up in response to factors that speed up aging, including chronic inflammation, obesity, mitochondrial dysfunction, and faulty autophagy [13].

5. Epigenetic Alterations

Changes in gene expression, known as epigenetic alterations, are a natural part of the aging process. These deviations interfere with normal cellular functions, increasing the risk of developing cancer and other age-related diseases. Alterations to the epigenome, which may affect gene expression, may occur as we age. Gene expression changes have the potential to alter cell function in undesirable ways. In the case of the immune system, for instance, epigenetic alterations may impair activation and suppress immune cells, resulting in a failure of the immune system and leaving us vulnerable to the onslaught of viruses. The rate at which epigenetic alterations occur may be slowed by caloric restriction, and inflammation has been shown to play a role in this [14]. The inflammation-metabolic-epigenetic triad is a positive feedback loop that reinforces already-severe epigenetic alterations.

Among the epigenetic changes that occur with age shifts in methylation patterns, which are often associated with a loss of heterochromatin, an increase in chromosomal fragility, and an increase in transcriptional variation, chromatin remodeling, and transcriptional noise. Epigenetic modifications in aging include chromatin remodeling, which makes chromosomes more brittle.

6. Loss of Proteostasis

To maintain the health of the proteome of the cell and the organism as a whole, the cell employs a mechanism called protein homeostasis, also known as proteostasis. Proteome proteins are normally protected by quality-control mechanisms such as protein production, degradation, and chaperoning; however, these processes become less robust with age [15]. This is a natural result of becoming older. Because aging compromises cell control and protein synthesis and removal, rising age is a critical risk factor for proteinopathies [16]. More than 50 disorders characterized by aberrant protein deposition have been linked to a breakdown in protein quality control, which is fundamental to proteostasis (proteinopathies). Proteostasis is a normal part of becoming older since it is the body’s first defensive mechanism in response to stress and because proteins are the building blocks for cellular repair and genome maintenance.

7. Deregulated Nutrient Sensing

To survive, it is crucial that our bodies sense and respond to changes in our dietary intake. A person’s cellular response to a given nutrition supply declines with age due to physiological changes that occur with time. This leads to further dysregulation [17] of critical metabolic processes. These mechanisms regulate our cells’ responses to ingested nutrients. Examples of receptors in these pathways include those that keep tabs on cellular energy production and the amounts of amino acids and carbs. The faster we age, the more likely it is that nutrients like amino acids or glucose have activated these nutrition-detecting pathways.

8. Mitochondrial Dysfunction

In both the fed and fasted phases, mitochondria play a crucial role in maintaining cellular homeostasis and calcium balance, as well as in the metabolism and interconversion of food substrates such as lipids, proteins, and carbs. This occurs because energy is generated through the mitochondrial process of oxidative phosphorylation. In reaction to environmental stress, they serve a crucial role in relaying information about the cell’s metabolic state to the nucleus and other cells in the body. Mitochondria may replicate independently and have their protein production machinery. However, disruptions to these pathways are common due to sickness and age. Both fusion and fission occur all the time, and a healthy balance between the two is essential for the cell.

9. Cellular Senescence

Cellular senescence (CS) is characterized by irreversible cell development arrest in typical and pathological physiological processes. Aging, tissue repair, tumor suppressor, and tumor promoter [18] are some of the processes that have been linked to this phenomenon, which is propelled by a complex interplay of factors.

Cellular senescence, which occurs due to various stress events, is the hallmark of aging. One of the effects of becoming older is that you start to notice this. This physiological process occurs naturally and aids in various functions, including growth, cancer prevention, wound healing, and more. But the buildup of senescent cells in a certain tissue or organ ultimately triggers the aging process in the overall body.

10. Compromised Autophagy

The cellular degradation process known as autophagy involves transporting cytoplasmic materials to lysosomes. This protects cells from the damaging effects of stress and assists cells in maintaining their energy balance. Multiple studies [19] have shown a link between autophagy and age-related neurodegeneration. A neuron’s post-mitotic nature makes it more susceptible to accumulating dysfunctional organelles and proteins. When added to the natural reduction in autophagic capability with age, it seems that autophagic failure lies at the heart of many neurodegenerative illnesses, a sad contradiction. The buildup of harmful aggregated proteins is a hallmark and a contributing element in the pathophysiology of many disorders [20].

While it is sometimes said that “decreased autophagy is bad” and “increased autophagy is helpful” when addressing the connection between autophagy and aging, this may be an excessively simple view of the relationship. Instead, creating the proper balance of autophagy, which will depend on the age of the tissue and the organism, is more likely to result in long-term health benefits [21].

11. Microbiome Disturbance

New understandings of the microbiome’s function have been made possible by the groundbreaking discoveries of high-throughput sequencing and metagenomic methods. One of the recent discoveries is that microbiota and host aging are interconnected in both directions. The human intestines have the largest surface area when it comes to direct contact with foreign antigens. The gut microbiome is a community of bacteria that lines the intestinal tract and is remarkable in its complexity and variety. Gut microbiota in good health can maintain metabolic homeostasis and immunological tolerance, allowing them to flourish inside the host.

In contrast, age-related chronic diseases, including obesity, cardiovascular disease, and neurological disorders, have been linked to aberrant modifications in the gut microbiota as a possible etiological factor. It’s important to cite this phrase. In recent years, evidence suggests that gut microbiota plays a significant role in aging [22].

12. Altered Mechanical Properties

The process of bone healing is greatly aided by mechanical stimulation, in addition to biological signals [23]. Aging is defined as the slow, cumulative, and irreversible process by which mechanical structures lose some or all of the capacity to perform the function they were designed for. This evolves gradually over time. Cellular and tissue mechanics are very important to the health of living organisms. When seen as a biocomposite, the mechanical parameters of a single cell are determined by the interdependent combination of the mechanical properties of the many cellular components. An accurate quantitative assessment of a cell’s mechanical properties requires knowledge about the cell’s current state, the measuring method, and the theoretical model used. Age-related increases in cell stiffness and declines in the ability of cells to undergo large reversible deformations are the most common cellular changes associated with aging. The overwhelming majority of cells go through this process. Cells’ capacity to rapidly reorganize their cellular skeleton’s functional components declines with age [24], and mechanical signal transmission is less efficient in older cells. Furthermore, aging cells are less effective in mechanical signal transduction than their younger counterparts.

13. Splicing Dysregulation

Alterations in the expression or activity of splicing factors are associated with human aging and longevity [25]. A newly discovered class of non-coding RNA species called circRNA has similarly been regulated in its production by splicing factors. Although the transcriptional activity of the host genes does not rise with age, it has been demonstrated that circular RNAs accumulate throughout time. Consequently, knocking down specific splicing components alters alternative splicing and causes an increase in the accumulation of circular RNAs [26].

14. Inflammation

The immune system, which evolved in living things to increase their chances of survival as a species, includes inflammation as a critical component. In the face of harmful substances like viruses, toxins, or allergies, the body’s first line of defense is acute inflammation [27]. Short duration is a defining feature of acute inflammation. However, additional defensive components are engaged to form a long-term immune response, known as chronic inflammation, when this complicated critical inflammatory response cannot be resolved and continues to remain. The lack of resolve characterizes this immunological response. The buildup of macrophages and lymphocytes as leukocytes [28] and other cellular components are characteristic of chronic inflammation, which often manifests in a muted form over a prolonged period. It is crucial to know that chronic inflammation is linked to changes in cellular redox state and the signaling pathways that lead to cell death [29].

Concluding Remarks

This article makes an attempt to identify and categorize the features of the aging process at the cellular and molecular levels. It found fourteen indicators that, taken together, make up the aging phenotype and are widely believed to have a role in the aging process. In order to establish a framework for future study on the molecular causes of aging and the development of medicines to extend the human health span, it is important to identify the features that are distinctive of aging.

References

[1]      K. Jin, “Modern biological theories of aging,” Aging Dis., vol. 1, no. 2, p. 72, 2010.

[2]      M. S. Fragala, “The physiology of aging and exercise,” in Exercise for Aging Adults, Springer, 2015, pp. 1–11.

[3]      G. Piedrafita, M. A. Keller, and M. Ralser, “The impact of non-enzymatic reactions and enzyme promiscuity on cellular metabolism during (oxidative) stress conditions,” Biomolecules, vol. 5, no. 3, pp. 2101–2122, 2015.

[4]      C. López-Otín, M. A. Blasco, L. Partridge, M. Serrano, and G. Kroemer, “The hallmarks of aging,” Cell, vol. 153, no. 6, pp. 1194–1217, 2013.

[5]      T. Schmauck-Medina et al., “New hallmarks of ageing: a 2022 Copenhagen ageing meeting summary,” Aging (Albany. NY)., vol. 14, no. undefined.

[6]      S.-H. Bae, C.-H. Kim, P. Leblanc, J. Moon, and K.-S. Kim, “Perspectives of aging study on stem cell,” Biomed. Dermatology, vol. 1, no. 1, pp. 1–5, 2017.

[7]      M. Cerletti, Y. C. Jang, L. W. S. Finley, M. C. Haigis, and A. J. Wagers, “Short-term calorie restriction enhances skeletal muscle stem cell function,” Cell Stem Cell, vol. 10, no. 5, pp. 515–519, 2012.

[8]      C. Kollman et al., “Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age,” Blood, J. Am. Soc. Hematol., vol. 98, no. 7, pp. 2043–2051, 2001.

[9]      E. Enwere, T. Shingo, C. Gregg, H. Fujikawa, S. Ohta, and S. Weiss, “Aging results in reduced epidermal growth factor receptor signaling, diminished olfactory neurogenesis, and deficits in fine olfactory discrimination,” J. Neurosci., vol. 24, no. 38, pp. 8354–8365, 2004.

[10]    Y. Hou et al., “Ageing as a risk factor for neurodegenerative disease,” Nat. Rev. Neurol., vol. 15, no. 10, pp. 565–581, 2019.

[11]    J. Vijg and C. Montagna, “Genome instability and aging: Cause or effect?,” Transl. Med. Aging, vol. 1, pp. 5–11, 2017, doi: https://doi.org/10.1016/j.tma.2017.09.003.

[12]    M. Fumagalli et al., “Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation,” Nat. Cell Biol., vol. 14, no. 4, pp. 355–365, 2012.

[13]    F. Rossiello, D. Jurk, J. F. Passos, and F. d’Adda di Fagagna, “Telomere dysfunction in ageing and age-related diseases,” Nat. Cell Biol., vol. 24, no. 2, pp. 135–147, 2022.

[14]    S. Maegawa et al., “Caloric restriction delays age-related methylation drift,” Nat. Commun., vol. 8, no. 1, pp. 1–11, 2017.

[15]    C. J. Proctor and I. A. J. Lorimer, “Modelling the role of the Hsp70/Hsp90 system in the maintenance of protein homeostasis,” PLoS One, vol. 6, no. 7, p. e22038, 2011.

[16]    L. C. Walker and H. LeVine, “Corruption and spread of pathogenic proteins in neurodegenerative diseases,” J. Biol. Chem., vol. 287, no. 40, pp. 33109–33115, 2012.

[17]    V. Micó, L. Berninches, J. Tapia, and L. Daimiel, “NutrimiRAging: Micromanaging Nutrient Sensing Pathways through Nutrition to  Promote Healthy Aging.,” Int. J. Mol. Sci., vol. 18, no. 5, Apr. 2017, doi: 10.3390/ijms18050915.

[18]    S. Da Silva-Álvarez and M. Collado, “Cellular Senescence,” R. A. Bradshaw and P. D. B. T.-E. of C. B. Stahl, Eds. Waltham: Academic Press, 2016, pp. 511–517.

[19]    C. Karabiyik, R. A. Frake, S. J. Park, M. Pavel, and D. C. Rubinsztein, “Autophagy in ageing and ageing-related neurodegenerative diseases,” Ageing Neurodegener. Dis., vol. 1, no. 1, p. 2, 2021.

[20]    M. Borsche et al., “Mitochondrial damage-associated inflammation highlights biomarkers in PRKN/PINK1 parkinsonism,” Brain, vol. 143, no. 10, pp. 3041–3051, 2020.

[21]    Y. Aman et al., “Autophagy in healthy aging and disease,” Nat. Aging, vol. 1, no. 8, pp. 634–650, 2021.

[22]    M. Kim and B. A. Benayoun, “The microbiome: an emerging key player in aging and longevity,” Transl. Med. aging, vol. 4, pp. 103–116, 2020.

[23]    H. Schell, D. R. Epari, J.-P. Kassi, H. Bragulla, H. J. Bail, and G. N. Duda, “The course of bone healing is influenced by the initial shear fixation stability,” J. Orthop. Res., vol. 23, no. 5, pp. 1022–1028, 2005.

[24]    M. N. Starodubtseva, “Mechanical properties of cells and ageing.,” Ageing Res. Rev., vol. 10, no. 1, pp. 16–25, Jan. 2011, doi: 10.1016/j.arr.2009.10.005.

[25]    B. P. Lee et al., “Changes in the expression of splicing factor transcripts and variations in alternative splicing are associated with lifespan in mice and humans,” Aging Cell, vol. 15, no. 5, pp. 903–913, 2016.

[26]    M. Bhadra, P. Howell, S. Dutta, C. Heintz, and W. B. Mair, “Alternative splicing in aging and longevity.,” Hum. Genet., vol. 139, no. 3, pp. 357–369, Mar. 2020, doi: 10.1007/s00439-019-02094-6.

[27]    M. O. Freire and T. E. Van Dyke, “Natural resolution of inflammation,” Periodontol. 2000, vol. 63, no. 1, pp. 149–164, 2013.

[28]    M. Chen and H. Xu, “Parainflammation, chronic inflammation, and age‐related macular degeneration,” J. Leukoc. Biol., vol. 98, no. 5, pp. 713–725, 2015.

[29]    H. Y. Chung, B. Sung, K. J. Jung, Y. Zou, and B. P. Yu, “The molecular inflammatory process in aging,” Antioxid. Redox Signal., vol. 8, no. 3–4, pp. 572–581, 2006.