A synopsis on aging—Theories, mechanisms and future prospects
Graphical abstract
Introduction
Aging is a topic that has captivated both scientists and philosophers throughout history. For Plato (428–347 BC), those who lived longer reached a philosophical understanding of mortal life, which lead to the desire in understanding everlasting ideas and truths, beyond the mortal world (Baars, 2012): “for wisdom and assured true conviction, a man is fortunate if he acquires them even on the verge of old age” (Cary et al., 1852). But perhaps the most accurate depiction of the human perception of aging comes from Giacomo Leopardi (1798–1837): “Old age is the supreme evil, because it deprives us of all pleasures, leaving us only the appetite for them, and it brings with it all sufferings. Nevertheless, we fear death, and we desire old age” (Leopardi et al., 1905).
In its broadest sense, aging merely refers to the changes that occur during an organisms’ life-span, though the rate at which these take place varies widely (Kirkwood, 2005). Consequently, such definition comprises changes that are not necessarily deleterious, such as wrinkles and graying hair in humans, which do not affect the individual’s viability. As Anton and co-workers put it (Anton et al., 2005), the phenotype is the end result of the interaction between genotype and external factors:[phenotype] = [genotype] + [(diet, lifestyle and environment)].
To differentiate these innocuous changes from those leading to increased risk of disease, disability or death, biogerontologists tend to use a more precise term – senescence – when describing aging (Dollemore, 2002). Senescence is, therefore, the progressive deterioration of bodily functions over time and normal human aging has been associated with a loss of complexity in a wide range of physiological processes and anatomic structures (Goldberger et al., 2002), including blood pressure (Kaplan et al., 1991), stride intervals (Hausdorff et al., 1997, Terrier and Dériaz, 2011), respiratory cycles (Peng et al., 2002, Schumann et al., 2010) and vision (Azemin et al., 2012), among others, such as postural dynamics (Manor et al., 2010), ultimately leading to decreased fertility and increased risk or mortality (Chesser, 2015, Lopez-Otin et al., 2013). Herein, however, we will refer to the more inclusive term “aging”, due to its extensive use in the literature. Though aging may be defined as the breakdown of self-organizing systems and reduced ability to adapt to the environment (Vasto et al., 2010), this is still a rather complex biological process with poorly understood mechanism(s) of regulation. Explanations of the aging mechanisms have become unexpectedly complicated. Where gerontologists once looked for a single, all-encompassing theory that could explain aging, such as a single gene or the decline of the immune system, they are now finding that multiple processes, combining and interacting on many levels, are on the basis of the aging process (Dollemore, 2002, Guarente, 2014) These processes take place not only at a cellular and molecular level, but also on tissues and organ systems. The relatively young science of aging is now becoming increasingly aware of the biochemical mechanisms that cause or react to aging (Yin and Chen, 2005). Hence, gerontology research currently stands on chemistry and biochemistry, as these are at the core of the aging processes. Advanced analytical studies are underway to observe and identify age-related changes in living organisms. Simultaneously, new synthetic and medicinal chemistry methodologies are yielding small molecule tools for the complete elucidation of complex biological pathways, as well as potential lifespan extending therapeutics (Ostler, 2012). However, to better understand how these could contribute to extend the knowledge of the mechanisms of aging, it is necessary to explore what are the prevailing theories as to why and how we age. Thus, we will extensively review and evaluate the prevalent theories of aging focusing on the major chemical, biological, psychological and pathological aspects of the process. The discussion of the different models of senescence will highlight the urgent need for system-wide approaches that provide a new, integrative view on aging research.
Section snippets
Theories of aging and how they shape the definitions of senescence
Many widespread theories as to why aging takes place abound. Generally, these consider it a programmed development (Tower, 2015a), though many disagree and the debate is still ongoing (Blagosklonny, 2013, Goldsmith, 2014, Goldsmith, 2012, Goldsmith, 2013). By 1990, Medvedev attempted to rationally classify the numerous theories of aging, which exceeded 300 (Medvedev, 1990). Aging has been attributed to molecular cross-linking (Bjorksten, 1968), free radical-induced damages (Harman, 1993),
The chemical interplay
Aging has been dubbed as a war raged between chemical and biochemical processes (Clarke, 2003), though a more accurate description might be that of a complex and rather interconnected gear mechanism. However, on the basis of this perspective, aging is fundamentally the end-result of unwanted chemical processes, which yields spontaneous side products of normal metabolism, including mutated, less active, and potentially toxic species of lipids, proteins, RNA, DNA and small molecules (Clarke, 2003
Models of senescence—what changes?
Aging is intrinsically complex and is characterized by numerous changes that take place at different levels of the biological hierarchy. There is no clear evidence which molecular, cellular or physiological changes are the most important drivers of the aging process and/or how they influence one another. Each mechanism tends to be – at least in part – supported by data indicating that it may play a role in the overall process. Nonetheless, the magnitude of an isolated mechanism is usually
Aging therapies—cure aging or die trying?
Is aging a disease? Aging is a process characterized by numerous pathologies, the sum of which inevitably leads to death and its biology by loss of homeostasis and the accumulation of molecular damage (Vijg and de Grey, 2014). Yet, if disease is defined as a disorder or abnormality of structure or function (Scully, 2004), than certainly aging is not a disease, as everyone suffers from it, though aging and disease often overlap. Hence, the question shifts towards should we cure aging? Opinions
Conclusions
(1) Biological aging, termed senescence, is one of the most complex biological processes. Theories of aging are generally classified as either program theories or damage theories. More recently, combined theories, in which the aging process is considered at a more comprehensive and global degree, have emerged, but definitive evidences are still elusive.
(2) The complexity of the aging process has led to the realization that an integrative approach is necessary to better understand the mechanisms
Conflict of interest
The authors declare that they have no conflict of interest.
Acknowledgements
This work was supported by national funds through FCT/MEC (PIDDAC) under project IF/00407/2013/CP1162/CT0023. Thanks are also due, for the financial support to CESAM (UID/AMB/50017), to Portuguese Science Foundation (FCT) FCT/MEC through national funds, and the co-funding by the FEDER, within the PT2020 Partnership Agreement and Compete 2020. This work was also funded by FCT through SFRH/BPD/102452/2014 under POCH funds, co-financed by the European Social Fund and Portuguese National Funds from
References (366)
- et al.
Cytochrome P450-2E1 promotes aging-related hepatic steatosis, apoptosis and fibrosis through increased nitroxidative stress
Free Radic. Biol. Med.
(2016) - et al.
Stem cells, mitochondria and aging
Biochim. Biophysi. Acta (BBA)—Bioenerg.
(2015) Advanced glycation endproducts—role in pathology of diabetic complications
Diab. Res. Clin. Pract.
(2005)- et al.
M-30 and 4HNE are sequestered in different aggresomesin the same hepatocytes
Exp. Mol. Pathol.
(2007) - et al.
The key role of growth hormone–insulin–IGF-1 signaling in aging and cancer
Crit. Rev. Oncol. Hematol.
(2013) - et al.
A new development in senescence
Cell
(2013) - et al.
Caloric restriction and intermittent fasting alter hepatic lipid droplet proteome and diacylglycerol species and prevent diabetes in NZO mice
Biochim. Biophys. Acta (BBA)—Mol. Cell Biol. Lipids
(2015) - et al.
C. elegans SIR-2.1 interacts with 14-3-3 proteins to activate DAF-16 and extend life span
Cell
(2006) - et al.
Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and meta-analysis
Lancet
(2004) - et al.
The aging kidney revisited: a systematic review
Ageing Res. Rev.
(2014)
Aging induced loss of stemness with concomitant gain of myogenic properties of a pure population of CD34+/CD45− muscle derived stem cells
Int. J. Biochem. Cell Biol.
What are the effects of maternal and pre-adult environments on ageing in humans, and are there lessons from animal models?
Mech. Ageing Dev.
Increased life span from overexpression of superoxide dismutase in Caenorhabditis elegans is not caused by decreased oxidative damage
Free Radic. Biol. Med.
Oral glycotoxins determine the effects of calorie restriction on oxidant stress, age-related diseases, and lifespan
Am. J. Pathol.
Cytochrome c nitration by peroxynitrite
J. Biol. Chem.
Telomerase protects Werner syndrome lineage-specific stem cells from premature aging
Stem Cell Rep.
The oxidative modification hypothesis of atherogenesis: an overview
Free Radic. Biol. Med.
Fibroblast cultures from healthy centenarians have an active proteasome
Exp. Gerontol.
The therapeutic promise of mesenchymal stem cells for liver restoration
Trends Mol. Med.
Aging as war between chemical and biochemical processes: protein methylation and the recognition of age-damaged proteins for repair
Ageing Res. Rev.
Analytical tools to assess aging in humans: the rise of Geri-Omics
TrAC Trends Anal. Chem.
Open-minded scepticism: inferring the causal mechanisms of human ageing from genetic perturbations
Ageing Res. Rev.
The fading electricity theory of ageing: the missing biophysical principle?
Ageing Res. Rev.
Dendritic spine changes associated with normal aging
Neuroscience
Oxidative damage to DNA in mammalian chromatin
Mutat. Res. /DNAging
Replicative senescence in the immune system: impact of the hayflick limit on T-Cell function in the elderly
Am. J. Hum. Genet.
Chapter five—adipose-derived stem cells and nerve regeneration: promises and pitfalls
EEG sleep patterns as a function of normal and pathological aging in man
J. Psychiatr. Res.
The menopause and aging, a comparative perspective
J. Steroid Biochem. Mol. Biol.
Nutritional factors and aging in demyelinating diseases
Genes Nutr.
New nucleophilic mechanisms of ros-dependent epigenetic modifications: comparison of aging and cancer
Aging Dis.
Targeted cargo delivery in senescent cells using capped mesoporous silica nanoparticles
Angew. Chem. Int. Ed.
Clinical Neurology of Aging
Aging is neither a failure nor an achievement of natural selection
Curr. Aging Sci.
Is there more to aging than mitochondrial DNA and reactive oxygen species?
FEBS J.
Can we delay aging? The biology and science of aging
Ann. N. Y. Acad. Sci.
Biology of Aging: Observations and Principles
Prohibitin couples diapause signalling to mitochondrial metabolism during ageing in C [thinsp]elegans
Nature
Is aging programed?
Aging Cell
Age-related rarefaction in the fractal dimension of retinal vessel
Neurobiol. Aging
Aging and the Art of Living
Why US adults use dietary supplements
JAMA Int. Med.
A review of aging theories and modern work perspectives
The Oxford Handbook of Work and Aging
Hip fracture incidence in relation to age, menopausal status, and age at menopause: prospective analysis
PLoS Med.
Insulin/IGF-I-signaling pathway: an evolutionarily conserved mechanism of longevity from yeast to humans
Am. J. Physiol. Endocrinol. Metab.
Updating the mitochondrial free radical theory of aging: an integrated view, key aspects, and confounding concepts
Antioxid. Redox Signal.
The critical role of metabolic pathways in aging
Diabetes
Systematic review: ageing and gastro‐oesophageal reflux disease symptoms, oesophageal function and reflux oesophagitis
Aliment. Pharmacol. Ther.
Are theories of aging important? Models and explanations in gerontology at the turn of the century
Handbook of Theories of Aging
Hypertrophy hypothesis as an alternative explanation of the phenomenon of replicative aging of yeast
FEMS Yeast Res.
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