Elsevier

Ageing Research Reviews

Volume 29, August 2016, Pages 90-112
Ageing Research Reviews

A synopsis on aging—Theories, mechanisms and future prospects

https://doi.org/10.1016/j.arr.2016.06.005Get rights and content

Highlights

  • Herein, we summarize the main theories and models of senescence.

  • An integrated view of the biochemical processes that accompany aging is provided.

  • We highlight and evaluate the most promising emergent anti-aging therapies.

  • The need for a multi-dimensional approach for understanding aging is discussed.

Abstract

Answering the question as to why we age is tantamount to answering the question of what is life itself. There are countless theories as to why and how we age, but, until recently, the very definition of aging – senescence – was still uncertain. Here, we summarize the main views of the different models of senescence, with a special emphasis on the biochemical processes that accompany aging.

Though inherently complex, aging is characterized by numerous changes that take place at different levels of the biological hierarchy. We therefore explore some of the most relevant changes that take place during aging and, finally, we overview the current status of emergent aging therapies and what the future holds for this field of research.

From this multi-dimensional approach, it becomes clear that an integrative approach that couples aging research with systems biology, capable of providing novel insights into how and why we age, is necessary.

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

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