Encyclopedia of Gerontology and Population Aging

Living Edition
| Editors: Danan Gu, Matthew E. Dupre

Aging Mechanisms

  • Graziamaria CorbiEmail author
  • Nicola Ferrara
Living reference work entry
DOI: https://doi.org/10.1007/978-3-319-69892-2_31-1



The mechanisms of aging in our species, or in closely related species, are interpreted in two completely different ways. As the two explanations are opposite and incompatible, they are presented in two separate sections of this entry, leaving to the reader any judgment about a conclusion.

Mechanisms of Aging According to Non-programmed (Nonadaptive) Aging Theories

These theories explain aging as caused by a progressive accumulation of several injuries insufficiently opposed by natural selection. In particular aging has been mainly attributed to free radical damages, changes in immunological functions, telomere shortening, and the presence of senescence genes in the DNA (da Costa et al. 2016; Davinelli et al. 2019). In fact, with advancing age, humans are continuously exposed to endogenous and environment antigens, which lead to a remodeling of both innate and acquired immune systems with a consequent establishment of chronic inflammatory state, the so-called inflammaging (Franceschi et al. 2000). Moreover, the imbalance of prooxidants and antioxidants is responsible for high ROS concentrations with indiscriminate damage to all cellular constituents, including DNA, proteins, and membranes (Conti et al. 2015a, b, 2017).

The balance between the production of ROS and the activation of the antioxidant defense system is crucial for the human physiology and the control of cellular homeostasis. ROS play an important role in signaling processes, but their overproduction generates oxidative stress. In fact, ROS can regulate cellular functions; in turn, their overproduction causes damage to cellular constituents, including DNA, proteins, and lipids, especially when occuring with insufficient antioxidant enzyme activity. The result is a progressive loss in function and aging (Sohal and Weindruch 1996).

Over the last decade, remarkable progress has been made to realize that chronic, low-grade inflammation is one of the major risk factors underlying aging. During their life, the cells progressively impair the ability to defend themselves from stress stimuli, and, as a consequence, there is an accumulation of oxidative damages in all cell constituents (Lardenoije et al. 2015; Corbi et al. 2016). Aging is associated with aberrant inflammatory responses in human. Specifically, basal levels of pro-inflammatory cytokines are elevated with aging, whereas anti-inflammatory mediators are reduced.

Increasing evidence suggests that chronic systemic inflammation and accumulating oxidative stress also play a role in developing many chronic diseases such as atherosclerosis, hypertension, and COPD (Stephens et al. 2009; Maio et al. 2012; Baldacci et al. 2012; Corbi et al. 2013; Conti et al. 2018). At the same time, metabolic changes show high influence in preventing or reducing the severity of age-related pathologies, suggesting that the management of these factors could have an effect on the progression of the diseases (Corbi et al. 2002, 2008, 2015; Ferrara et al. 2005).

In fact aging is characterized by increasing prevalence of cardiovascular diseases, related to pathophysiological changes distinguishing “senile” heart. In particular, in the elderly, cardiac apoptosis and necrosis, proliferation of myocyte nuclei, increased myocyte volume, and connective tissue accumulation are observed. Another marker of “aged heart” is represented by attenuated induction of cell-protective mechanisms, such as antioxidants and heat shock proteins, in response to pathologic insults. In fact, the pathophysiology of aging and age-related diseases involves oxidative stress as an early stage in its development as confirmed by a decrease in antioxidant defenses and an increase in oxidative damage.

In particular aging is characterized by activation of several signaling molecules, such as NF-𝜅B, Forkhead boxO, superoxide dismutases, and Klotho (Conti et al. 2015a, b). All these processes are regulated by sirtuins, a family of NAD + -dependent deacetylases initially identified as regulators of the aging process (Nakagawa and Guarente 2014). SIRT1, the best-characterized member of the family, is involved in many functions of human physiology, including DNA repair, cell cycle regulation, apoptosis, gene expression, and aging. SIRT1 can modulate the cellular stress response directly deacetylating some proteins and regulating their expression. Furthermore, this enzyme modulates the threshold of cell death in the setting of exogenous stress, including oxidative damage, and regulation of other targets linked to cell death.

Then the ability of SIRT1 to modulate stress resistance is multifaceted, and it is not only linked to oxidative stress but also to other stressful stimuli (Conti et al. 2012). Some authors showed that Sirt1 provides protection against apoptosis and plays an essential role in mediating survival of cardiac myocytes and neurons under stress in vitro (Pillai et al. 2014). SIRT1 also regulates immune responses via NF-kB signaling and in this way also controls the ROS production. The NF-kB signaling is a crucial pathway of immune defense system and an inducer of inflammatory responses. The NF-kB system is involved in many housekeeping and survival functions during cellular stress, e.g., by controlling apoptosis, proliferation, and energy metabolism.

Both SIRT1 and oxidative stress are known to be able to regulate NF-kB signaling and are crucially involved in the maintenance of cellular homeostasis. Moreover, several studies demonstrated that NF-kB signaling is activated during aging (Davinelli et al. 2016). The cross talk between oxidative stress and inflammation is a complex process, and there are studies reporting that ROS can stimulate inflammation via the activation of inflammasomes and the production of IL-1b and IL-18 cytokines, which subsequently trigger inflammatory responses. Many studies have also demonstrated that SIRT1 is a potent intracellular inhibitor of oxidative stress and inflammatory responses. In particular, SIRT1 is a powerful inhibitor of NF-kB signaling, and thus, it suppresses inflammation (Davinelli et al. 2019).

Indeed sirtuins also seem to mediate the cellular antioxidant response induced by caloric restriction, physical activity (Russomanno et al. 2017), and dietary phytochemicals (Corbi et al. 2002, 2018; Davinelli et al. 2018). Based on these results, interesting models focused on antioxidant supplementation as an antiaging strategy have been developed (Corbi et al. 2018).

Mechanisms of Aging According to Programmed (Adaptive) Aging Theory

This theory explains aging as favored by natural selection at the supra-individual level. This means that aging is determined and modulated by specific genes forged by natural selection. The supra-individual selection that would be at the origin of the phenomenon is not the subject of this exposition and is therefore not discussed here. Furthermore, the specific mechanisms that would determine aging are illustrated as proposed by the telomere theory (Fossel 2004).

After decades in which dominant opinion, considered scientifically sound, was that normal cells were able to duplicate themselves without limits, in 1961 an important work demonstrated that there were defined restrictions in cell duplication capacities (Hayflick and Moorhead 1961). For the causes of this limit (Hayflik’s limit), shown to be in the nucleus, Olovnikov hypothesized that as the DNA duplicating enzyme was unable to duplicate the whole molecule and this shortened the molecule at each replication, after a certain number of duplications, the shortened DNA blocked the ability of cell to replicate (Olovnikov 1973). Furthermore, it was necessary to hypothesize the existence of an enzyme, afterward called telomerase, able to restore the length of the molecule, to justify the existence of cells, as those of germ line, capable of numberless duplications (Olovnikov 1973).

Subsequently, it was found, for the first time in a protozoan species, that each end of a DNA molecule, called telomere, shows the monotone repetition of a simple sequence (Blackburn and Gall 1978). The enzyme telomerase, which added nucleotide sequences to the telomere, was identified, and so the existence of cells capable of numerous or numberless divisions, as stem and germ line cells, was explained (Greider and Blackburn 1985).

In cells where telomerase is inactive, as telomeres shorten at each duplication, an infinite number of duplications are impossible. However, before telomeres reach their minimum length, two phenomena are described (Fig. 1):
  • Gradual cell senescence (or telomere position effect). The telomere is covered by a heterochromatin hood with a length that does not vary at each duplication. As the telomere shortens, this hood slides over the subtelomeric region which has general regulatory functions and is somehow repressed. This causes a progressive alteration of cell functions, extracellular secretions included (Fossel 2004). For a more detailed exposition, the entry Gradual cell senescence should be seen.

  • Cell senescence. Telomeres oscillate between two states: the “capped” state, when it is covered by the heterochromatin hood, and the “uncapped” state. The duration of the second state, which is related to the grade of telomere shortening, is vulnerable to replicative senescence, while the other state is resistant to this transformation. Even when telomeres have their maximum length, there is a short phase in which they are uncapped and vulnerable to cell senescence (Blackburn 2000).

Fig. 1

Scheme of the transformation of a young tissue into an old tissue. The progressive telomere shortening determines an increasing number of cells in gradual senescence and in cell senescence. There are related alterations of intercellular fluids and sufferings of normal cells

Replicative senescence was later shown to be part of a specific cellular program, the cell senescence (Ben-Porath and Weinberg 2005). Cell senescence is characterized by replicative senescence and by the alterations of gradual cell senescence in their highest degree. The entry subtelomere-telomere-telomerase system offers a more detailed exposition.

The progressive increase of cells unable to duplicate and/or with altered cell functions in various degrees increasingly compromises a dynamic system in which cell turnover is the dominant element. Indeed, disregarding the cases in which cells die from accidental or pathological events, most cells die for various types of programmed cell death (PCD), e.g., keratinization of epidermis or hair cells, detachment of cells from the lining of intestines or other body cavities, and apoptosis. About the last type of PCD, it is documented for many tissues that an important function of apoptosis in vertebrates is related to the cell turnover in healthy organs (Libertini 2009). The loss of cells caused by the various types of PCD must be balanced by an equivalent duplication of appropriate stem cells. The phenomenon is massive: it has been estimated that every day PCD cases eliminate about 50–70 billion cells (i.e., about 580,000–810,000 cells/second) and that in 1 year “a mass of cells equal to almost our entire body weight” is replaced (Reed 1999). The rhythm of cell turnover varies greatly depending on cell type and organ. For example, in our species, the cells of the intestinal epithelium are replaced every 3 to 6 days, while the bone has a turnover time of about 10 years (Alberts et al. 2013), and for other cell types, there are intermediate rhythms (Richardson et al. 2014). For cell types that do not show turnover (e.g., most neurons), it is important to consider that their functionality and vitality depend on other cells that are subjected to turnover (Libertini and Ferrara 2016).

As a consequence, cell senescence and gradual cell senescence progressively compromise the function and structure of tissues and organs causing an atrophic syndrome characterized by:
  1. (a)

    reduced mean cell duplication capacity and slackened cell turnover;

  2. (b)

    reduced number of cells (atrophy);

  3. (c)

    substitution of missing specific cells with non-specific cells;

  4. (d)

    hypertrophy of the remaining specific cells;

  5. (e)

    altered functions of cells with shortened telomeres or definitively in noncycling state;

  6. (f)

    alterations of the surrounding milieu and of the cells depending from the functionality of the senescent or missing cells;

  7. (g)

    vulnerability to cancer because of dysfunctional telomere-induced instability ... (Libertini 2014)

Atrophic syndrome in the various tissues and organs causes a series of progressive disorders that are typical of the senile condition (Fig. 2). These troubles are generally considered improperly as distinct diseases by those who do not accept the idea of aging as a unitary phenomenon with its own physiology that is well distinguishable and describable. These alterations caused by the mechanisms of aging are of two types:
  • Direct, when the functional cells of the tissue are subject to turnover and the alterations deriving from telomere shortening directly affect these cells.

  • Indirect, when the functional cells of the tissue are not subject to turnover but depend for their functionality and vitality on other cells that are subject to turnover. These latter cells are affected by the alterations deriving from the telomere shortening. So, the functional cells are indirectly damaged. This second type of aging is detailed in the entry Aging for perennial cells.

Fig. 2

Scheme of aging mechanisms at organismal level

It is also to underline (i) the above said alterations are influenced by factors (“risk factors”) that increase the need for cellular duplication and so accelerate aging (e.g., harmful substances, unhealthy lifestyles, smoke) and (ii) this acceleration is also reduced or cancelled from other factors, definable as “protective factors” (e.g., “protective drugs,” healthy lifestyles). In this perspective, it is important to clarify that this second group of factors reduces the abnormal acceleration of aging, but there is no evidence and is unlikely that they are able to reduce the physiological rhythm of aging.

Another point to underline is that telomere shortening when it reaches critical levels increases the vulnerability to cancer (DePinho 2000). However, in natural conditions and for a human population, even if 20% of the studied population survived at the age of 70 years, cancer cases did not show a detectable incidence (Hill and Hurtado 1996).

It is possible to describe how the atrophic syndrome progressively alters the function and anatomy of each tissue and organ. For brevity, here only part of the evidence related to some organs will be reported:


In the derma of old human subjects, a general reduction of all its components (dermal fibroblasts, mast cells, eccrine glands, hair, Langerhans cells, melanocytes, capillaries, blood vessels within the reticular dermis, etc.) is documented. Dermal-epidermal junction, where stem cells are located and which shows a corrugated surface in young subjects, appears flattened, and the rate of epidermal renewal is reduced. These phenomena are a likely consequence of the exhaustion of specific stem cells (Griffiths 1998).


As stated by Dieppe and Tobias (1998): “Once middle age is reached, the total amount of calcium in the skeleton (i.e., bone mass) starts to decline with age ... This is associated with changes in skeletal structure, resulting in it becoming weaker and more prone to sustaining fractures. For example, the bony cortex becomes thinner due to expansion of the inner medullary cavity, the trabecular network disintegrates, and there is an accumulation of microfractures. ... Bone loss in the elderly is largely a result of excess osteoclast activity, which causes both an expansion in the total number of remodeling sites and an increase in the amount of bone resorbed per individual site. .... Bone loss in the elderly is also thought to involve an age-related decline in the recruitment and synthetic capacity of osteoblasts” (Dieppe and Tobias 1998).

Involutional bone loss ... starts between the ages of 35 and 40 in both sexes, but in women there is an acceleration of bone loss in the decade after menopause. Overall, women lose 35 to 50 percent of trabecular and 25 to 30 percent of cortical bone mass with advancing age, whereas men lose 15 to 45 percent of trabecular and 5 to 15 percent of cortical bone. ... Bone loss starts between the ages of 35 and 40 years in both sexes, possibly related to impaired new bone formation, due to declining osteoblast function (Francis 1998).

Gastrointestinal System

In each intestinal crypt, there are four to six stem cells that allow the continuous rapid turnover of small intestine epithelium (Barker et al. 2007). It is known for a long time that the transit time for cells from crypts to villous tips is increased in older individuals and that intestinal villi are shorter, broader, and with less cellularity (Webster 1978). These alterations of the intestinal functionality are surely due to the declining duplication capacity of the crypt stem cells, as hypothesized long since (Webster 1978).

Future Research Directions

Because a great body of evidence supports both antagonistic theories more studies should be performed to better understand the factors involved in aging mechanism. In fact, the knowledge of the factors responsible of aging genesis or progression could address possible therapeutic (pharmacological, genetic, etc.) interventions.


The mechanisms of aging in our species, or in closely related species, can be interpreted in two completely different ways. In this chapter, the mechanisms of aging according to non-programmed or programmed aging theories are discussed in two separate sections because opposite and incompatible. Any conclusive judgment on the most persuasive theory is left to the reader.



  1. Alberts B, Bray D, Hopkin K et al (eds) (2013) Essential cell biology, 4th edn. Garland Science, New YorkGoogle Scholar
  2. Baldacci S, Maio S, Simoni M et al (2012) The ARGA study with general practitioners: impact of medical education on asthma/rhinitis management. Respir Med 106(6):777–785.  https://doi.org/10.1016/j.rmed.2012.02.013CrossRefGoogle Scholar
  3. Barker N, van Es JH, Kuipers J et al (2007) Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449:1003–1007.  https://doi.org/10.1038/nature06196CrossRefGoogle Scholar
  4. Ben-Porath I, Weinberg R (2005) The signals and pathways activating cellular senescence. Int J Biochem Cell Biol 37:961–976.  https://doi.org/10.1016/j.biocel.2004.10.013CrossRefGoogle Scholar
  5. Blackburn EH (2000) Telomere states and cell fates. Nature 408:53–56.  https://doi.org/10.1038/35040500CrossRefGoogle Scholar
  6. Blackburn EH, Gall JG (1978) A tandemly repeated sequence at the termini of the extrachromosomal ribosomal RNA genes in Tetrahymena. J Mol Biol 120:33–53CrossRefGoogle Scholar
  7. Conti V, Corbi G, Russomanno G et al (2012) Oxidative stress effects on endothelial cells treated with different athletes’ sera. Med Sci Sports Exerc 44(1):39–49.  https://doi.org/10.1249/MSS.0b013e318227f69cCrossRefGoogle Scholar
  8. Conti V, Corbi G, Manzo V et al (2015a) Sirtuin 1 and aging theory for chronic obstructive pulmonary disease. Anal Cell Pathol (Amst) 2015:897327.  https://doi.org/10.1155/2015/897327Google Scholar
  9. Conti V, Corbi G, Simeon V et al (2015b) Aging-related changes in oxidative stress response of human endothelial cells. Aging Clin Exp Res 27(4):547–553. https://doi.org/.  https://doi.org/10.1007/s40520-015-0357-9CrossRefGoogle Scholar
  10. Conti V, Forte M, Corbi G et al (2017) Sirtuins: possible clinical implications in cardio and cerebrovascular diseases. Curr Drug Targets 18(4):473–484.  https://doi.org/10.2174/1389450116666151019095903CrossRefGoogle Scholar
  11. Conti V, Corbi G, Manzo V et al (2018) SIRT1 activity in peripheral blood mononuclear cells correlates with altered lung function in patients with chronic obstructive pulmonary disease. Oxidative Med Cell Longev 2018:9391261.  https://doi.org/10.1155/2018/9391261Google Scholar
  12. Corbi G, Carbone S, Ziccardi P et al (2002) FFAs and QT intervals in obese women with visceral adiposity: effects of sustained weight loss over 1 year. J Clin Endocrinol Metab 87(5):2080–2083.  https://doi.org/10.1210/jcem.87.5.8516CrossRefGoogle Scholar
  13. Corbi G, Acanfora D, Iannuzzi GL et al (2008) Hypermagnesemia predicts mortality in elderly with congestive heart disease: relationship with laxative and antacid use. Rejuvenation Res 11(1):129–138.  https://doi.org/10.1089/rej.2007.0583CrossRefGoogle Scholar
  14. Corbi G, Bianco A, Turchiarelli V et al (2013) Potential mechanisms linking atherosclerosis and increased cardiovascular risk in COPD: focus on Sirtuins. Int J Mol Sci 14(6):12696–12713.  https://doi.org/10.3390/ijms140612696CrossRefGoogle Scholar
  15. Corbi G, Gambassi G, Pagano G et al (2015) Impact of an innovative educational strategy on medication appropriate use and length of stay in elderly patients. Medicine (Baltimore) 94(24):e918.  https://doi.org/10.1097/MD.0000000000000918CrossRefGoogle Scholar
  16. Corbi G, Conti V, Davinelli S et al (2016) Dietary phytochemicals in neuroimmunoaging: a new therapeutic possibility for humans? Front Pharmacol 7:364.  https://doi.org/10.3389/fphar.2016.00364CrossRefGoogle Scholar
  17. Corbi G, Conti V, Komici K et al (2018) Phenolic plant extracts induce Sirt1 activity and increase antioxidant levels in the Rabbit’s heart and liver. Oxidative Med Cell Longev 2018:2731289.  https://doi.org/10.1155/2018/2731289CrossRefGoogle Scholar
  18. da Costa JP, Vitorino R, Silva GM et al (2016) A synopsis on aging—theories, mechanisms and future prospects. Ageing Res Rev 29:90–112.  https://doi.org/10.1016/j.arr.2016.06.005CrossRefGoogle Scholar
  19. Davinelli S, Maes M, Corbi G et al (2016) Dietary phytochemicals and neuro-inflammaging: from mechanistic insights to translational challenges. Immun Ageing 13(14):16.  https://doi.org/10.1186/s12979-016-0070-3CrossRefGoogle Scholar
  20. Davinelli S, Corbi G, Zarrelli A et al (2018) Short-term supplementation with flavanol-rich cocoa improves lipid profile, antioxidant status and positively influences the AA/EPA ratio in healthy subjects. J Nutr Biochem 61:33–39. https://doi.org/.  https://doi.org/10.1016/j.jnutbio.2018.07.011CrossRefGoogle Scholar
  21. Davinelli S, Trichopoulou A, Corbi G et al (2019) The potential nutrigeroprotective role of Mediterranean diet and its functional components on telomere length dynamics. Ageing Res Rev 49:1–10.  https://doi.org/10.1016/j.arr.2018.11.001CrossRefGoogle Scholar
  22. DePinho RA (2000) The age of cancer. Nature 408:248–254.  https://doi.org/10.1038/35041694CrossRefGoogle Scholar
  23. Dieppe P, Tobias J (1998) Bone and joint aging. In: Tallis RC, Fillit HM, Brocklehurst JC (eds) Brocklehurst’s textbook of geriatric medicine and gerontology, 5th edn. Churchill Livingstone, New York, pp 1131–1136Google Scholar
  24. Ferrara N, Abete P, Corbi G et al (2005) Insulin-induced changes in beta-adrenergic response: an experimental study in the isolated rat papillary muscle. Am J Hypertens 18(3):348–353.  https://doi.org/10.1016/j.amjhyper.2004.10.006CrossRefGoogle Scholar
  25. Fossel MB (2004) Cells, aging and human disease. Oxford University Press, OxfordGoogle Scholar
  26. Franceschi C, Bonafè M, Valensin S et al (2000) Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci 908:244–254CrossRefGoogle Scholar
  27. Francis RM (1998) Metabolic bone disease. In: Tallis RC, Fillit HM, Brocklehurst JC (eds) Geriatric medicine and gerontology, 5th edn, Churcill Livingstone, New York, pp. 1137–1154Google Scholar
  28. Greider CW, Blackburn EH (1985) Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell 51:405–413CrossRefGoogle Scholar
  29. Griffiths CEM (1998) Aging of the skin. In: Tallis RC, Fillit HM, Brocklehurst JC (eds) Geriatric medicine and gerontology, 5th edn, Churcill Livingstone, New York, pp. 1293–1298Google Scholar
  30. Hayflick L, Moorhead PS (1961) The serial cultivation of human diploid cell strains. Exp Cell Res 25:585–621CrossRefGoogle Scholar
  31. Hill K, Hurtado AM (1996) Ache life history. Aldine De Gruyter, New YorkGoogle Scholar
  32. Lardenoije R, Iatrou A, Kenis G et al (2015) The epigenetics of aging and neurodegeneration. Prog Neurobiol 131:21–64.  https://doi.org/10.1016/j.pneurobio.2015.05.002CrossRefGoogle Scholar
  33. Libertini G (2009) The role of telomere-telomerase system in age-related fitness decline, a tameable process. In: Mancini L (ed) Telomeres: function, shortening and lengthening. Nova Science Publishers, New York, pp 77–132Google Scholar
  34. Libertini G (2014) Programmed aging paradigm: how we get old. Biochem Mosc 79(10):1004–1016.  https://doi.org/10.1134/S0006297914100034CrossRefGoogle Scholar
  35. Libertini G, Ferrara N (2016) Aging of perennial cells and organ parts according to the programmed aging paradigm. Age (Dordr) 38(2):35.  https://doi.org/10.1007/s11357-016-9895-0CrossRefGoogle Scholar
  36. Maio S, Baldacci S, Simoni M et al (2012) Impact of asthma and comorbid allergic rhinitis on quality of life and control in patients of Italian general practitioners. J Asthma 49(8):854–861.  https://doi.org/10.3109/02770903.2012.716471CrossRefGoogle Scholar
  37. Nakagawa T, Guarente L (2014) SnapShot: sirtuins, NAD, and aging. Cell Metab 20(1):192–192.e1.  https://doi.org/10.1016/j.cmet.2014.06.001CrossRefGoogle Scholar
  38. Olovnikov AM (1973) A theory of marginotomy: the incomplete copying of template margin in enzyme synthesis of polynucleotides and biological significance of the problem. J Theor Biol 41:181–190CrossRefGoogle Scholar
  39. Pillai VB, Sundaresan NR, Gupta MP (2014) Regulation of Akt signaling by sirtuins: its implication in cardiac hypertrophy and aging. Circ Res 114(2):368–378.  https://doi.org/10.1161/CIRCRESAHA.113.300536CrossRefGoogle Scholar
  40. Reed JC (1999) Dysregulation of apoptosis in Cancer. J Clin Oncol 17:2941–2953CrossRefGoogle Scholar
  41. Richardson BR, Allan DS, Le Y (2014) Greater organ involution in highly proliferative tissues associated with the early onset and acceleration of ageing in humans. Experim Geront 55:80–91.  https://doi.org/10.1016/j.exger.2014.03.015CrossRefGoogle Scholar
  42. Russomanno G, Corbi G, Manzo V et al (2017) The anti-ageing molecule sirt1 mediates beneficial effects of cardiac rehabilitation. Immun Ageing 14:7.  https://doi.org/10.1186/s12979-017-0088-1CrossRefGoogle Scholar
  43. Sohal RS, Weindruch R (1996) Oxidative stress, caloric restriction, and aging. Science 273(5271):59–63CrossRefGoogle Scholar
  44. Stephens JW, Khanolkar MP, Bain SC (2009) The biological relevance and measurement of plasma markers of oxidative stress in diabetes and cardiovascular disease. Atherosclerosis 202(2):321–329.  https://doi.org/10.1016/j.atherosclerosis.2008.06.006CrossRefGoogle Scholar
  45. Webster SGP (1978) The gastrointestinal system – c. The pancreas and the small bowel. In: Brocklehurst JC (ed) Textbook of geriatric medicine and gerontology, 2nd edn. Churchill Livingstone, New YorkGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Medicine and Health SciencesUniversity of MoliseCampobassoItaly
  2. 2.Department of Translational Medical SciencesFederico II UniversityNaplesItaly

Section editors and affiliations

  • Giacinto Libertini
    • 1
  1. 1.ASL NA2 NordItalian National Health ServiceFrattamaggioreItaly