Aging is a process that includes a gradual loss of physiological integrity, which impairs body functions and increases susceptibility to various diseases and pathologies. Research in the field of aging has advanced significantly recently, especially with the discovery that the rate of aging is to some extent under the control of genetic pathways and biochemical processes that have been evolutionarily preserved. This review highlights nine key hallmarks of aging in different organisms, focusing on aging in mammals. These features include genomic instability, telomere shortening, epigenetic changes, proteostasis imbalance, nutrient uptake problems, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and changes in intercellular communication. Identifying the links between these features and their contribution to aging is a challenge we face, and the ultimate goal is to discover pharmaceutical targets that would improve health during aging with minimal side effects.
The Biology of Aging

Aging is a complex process that occurs as a result of many factors, including environmental influences, random events, genetic and epigenetic factors that affect different types of cells and tissues throughout life. One of the fundamental characteristics of aging is inflammation, which is associated with most age-related diseases. Inflammation describes a long-term, systemic process that occurs in tissues and organs during aging, often without the presence of overt infection (known as “sterile” inflammation). This is a significant risk factor for many health problems and increased mortality in the elderly. Epidemiological data show that a state of mild inflammation, as revealed by elevated levels of inflammatory markers such as C-reactive protein and interleukin-6 (IL-6), is associated with various aspects of aging, including changes in body composition, energy balance, immune response and health of the nervous system. The causes and role of inflammation in these processes are still not fully elucidated, which highlights the importance of identifying the pathways that regulate inflammation associated with aging in order to assess the potential benefit of modulating the inflammatory response in the elderly.
Inflammation

Inflammation may be useful as a short-term immune response to adverse events, such as traumatic tissue injury or pathogen invasion. This response is important because it helps repair, restore and adapt the tissue to the discomfort. However, during aging, acute inflammatory responses to pathogenic molecular patterns may become less effective, which may increase the risk of infections.
Chronic inflammation has many of the characteristics of acute inflammation, but is usually low-intensity and long-lasting, which can lead to tissue degeneration. There are several mechanisms of chronic inflammation: the first is the increased production of reactive molecules by leukocytes directed at pathogens, which can cause damage to structural and cellular elements of tissues. Another mechanism involves damage to non-immune and activation of immune cells that produce cytokines that can enhance or modulate the inflammatory response and alter tissue functions. A third mechanism is interference with “anabolic signaling,” which can affect many processes in the tissue.
Many aging tissues are likely to be in a state of chronic inflammation, even without the presence of infection. Although the above mechanisms are significant, it is important to note that the inflammatory response can arise from different sources and that their mutual interactions require additional research to be fully understood.
Mitochondrial Dysfunction
Mitochondria play an important role in the inflammatory process and the activation of the Nlrp3 inflammasome. The Nlrp3 inflammasome is a protein complex that can activate procaspase-1 as a result of cellular danger, leading to processing and upregulation of the proinflammatory cytokines IL-1β and IL-18. Most stimuli that activate the Nlrp3 inflammasome induce the generation of mitochondrial reactive oxygen species.
Mitochondria, as former phylogenetic bacterial symbionts of early eukaryotic cells, when damaged, release molecular patterns associated with mitochondrial damage. These patterns, such as formyl peptides and mitochondrial DNA, share evolutionarily conserved similarities with bacterial pathogens and may be released into circulation as potent activators of innate immunity and the Nlrp3 inflammasome.
Cardiolipin, found in mitochondria and bacteria, can act as an endogenous molecule associated with the pathogenic pattern after mitochondrial dysfunction and activate the pro-inflammatory pathway from the Nlrp3 inflammasome.
Oxidative Stress

The mitochondrial free radical theory of aging proposes that progressive mitochondrial dysfunction that occurs with age leads to increased production of reactive oxygen species (ROS), which in turn causes further mitochondrial deterioration and global cell damage (Harman, 1965). More evidence supports the role of ROS in aging, but here we focus on the developments of the last 5 years, which have prompted an intensive reappraisal of the mitochondrial free radical theory (Hekimi et al., 2011). Of particular importance was the unexpected finding that increasing ROS can extend the lifespan of yeast and C. elegans (Doonan et al., 2008; Mesquita et al., 2010; Van Raamsdonk and Hekimi, 2009). Similarly, genetic manipulations in mice that increase mitochondrial ROS and oxidative damage do not accelerate aging (Van Remmen et al., 2003; Zhang et al., 2009), mice with increased antioxidant defenses do not show increased lifespan (Perez et al., 2009), and, finally, genetic manipulations that impair mitochondrial function, but do not increase ROS, accelerate aging (Edgar et al., 2009; Hiona et al., 2010; Kujoth et al., 2005; Trifunovic et al., 2004). ; Vermulst et al., 2008). These and other data paved the way for re-examination of the role of ROS in aging (Ristow and Schmeisser, 2011). Indeed, in parallel and specifically with the work on the deleterious effect of ROS, the field of intracellular signaling has gathered solid evidence for the role of ROS in driving proliferation and survival in response to physiological signals and stress conditions (Sena and Chandele, 2012). These two lines of evidence can be reconciled if ROS is considered a stress-induced survival signal, conceptually similar to AMP or NAD+ (see “Deregulated Nutrient Sense”). In this sense, the primary effect of ROS will be to activate compensatory homeostatic responses. As chronological age progresses, cellular stress and damage increase and ROS levels rise in parallel in an attempt to maintain survival. Above a certain threshold, ROS levels betray their original homeostatic purpose and eventually exacerbate, rather than ameliorate, age-related damage (Hekimi et al., 2011). This new conceptual framework can accommodate the apparently conflicting evidence regarding positive, negative, or neutral effects of ROS on aging.
Telomere Shortening
The accumulation of DNA damage over the years appears to reflect on the gene in a random manner, but there are certain chromosomal regions, such as telomeres, that are particularly susceptible to deterioration with age. Replicating DNA polymerases lack the ability to completely replicate the terminal ends of linear DNA molecules, a function that is characteristic of a specialized DNA polymerase known as telomerase. However, most mammalian somatic cells do not express telomerase, leading to a progressive and cumulative loss of telomeric protective sequences at chromosome ends. Telomere depletion explains the limited proliferative capacity of some cell types cultured in vitro, which is called replicative senescence or the Heiflick limit. Indeed, expression of telomerase beyond its normal function is sufficient to confer immortality to otherwise mortal cells without inducing oncogenic transformation. It is important to note that telomere shortening has also been observed during normal aging in both humans and mice.
Conclusion
“Inflammaging” describes low-intensity chronic inflammation during aging and is a very significant risk factor for disease and mortality in the elderly, but it can be prevented and cured. Acute, transient inflammation may be useful as a basic immune response to noxious conditions such as traumatic tissue injury or pathogen invasion; chronic inflammation is usually low-intensity and persistent, leading to responses leading to tissue damage/degeneration.
References:
- López-OtÃn, C., Blasco, M.A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217.
- Harman, D. (1956). Aging: a theory based on free radical and radiation chemistry. Journal of Gerontology, 11(3), 298-300.
- Franceschi, C., & Campisi, J. (2014). Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, 69(Suppl_1), S4-S9.
- Blackburn, E.H., & Epel, E.S. (2012). Telomeres and adversity: Too toxic to ignore. Nature, 490(7419), 169-171.