What Causes Aging? How Much Have We Learned in Recent Years?
Surprisingly, the biology of aging is becoming clear.
Evidence That There are Molecular Mechanisms of Aging
Research at universities and in the private sector has made significant in-roads into the causes of aging at the cellular and molecular level. Changes at this level occur in our cells as we get older and seem to have a large impact on the body as a whole, contributing to or perhaps directly causing the age-related diseases that are house-hold names. These changes cumulatively described as biological aging come from two sources: accumulation of damage and programmed aging. Some examples of accumulation of damage are metabolic waste accumulating with age causing mitochondrial dysfunction and U.V. radiation causing damage to DNA, some of which goes unrepaired. Programmed aging is exemplified by biological clocks, such as telomeres, the protective caps at the end of chromosomes, which get shorter with each cellular division, eventually leading to senescence (the inability of the cell to replicate) after a certain number of divisions known as the Hayflick limit [1]. A more recently discovered biological clock, called the Horvath clock, consists of epigenetic modifications which turn on or off genes that influence the rate of aging [2]. Together, aging from unrepaired damage and programmed aging cause a complex variety of dysfunctions at the cellular level known as the nine hallmarks of aging [1], and it is thought that these hallmarks collectively lead to the systemic changes and dysfunctions that we recognize as aging.
The Nine Hallmarks of Aging are:
· Genomic instability: Damage to the nuclear DNA and mitochondrial DNA, as well as to the nuclear lamina occurs due to extrinsic factors, such as viruses, UV damage, and chemicals, and from intrinsic factors, such as DNA replication errors, reactive oxygen species (ROS), and spontaneous hydrolysis. Although there are built-in DNA repair mechanisms, genomic damage accumulates with age, and can cause “premature aging” if it accumulates quickly [1].
· Telomere attrition: Telomeres are sections of repeated DNA sequences that serve as protective caps at the ends of chromosomes. Telomeres get shorter with each cellular division, eventually leading to a loss of replicative capacity, aka the Hayflick limit, at which point cells enter either senescence (a state of halted cellular division) or apoptosis (programmed cell death). Telomere shortening is correlated with physiological aging, and activating an enzyme called telomerase, which lengthens telomeres, has been shown to increase median lifespan, although not extending maximum lifespan [3]. Unfortunately, DNA damage accumulates to a greater degree in telomeres than other DNA because of the presence of complexes called shelterins. Shelterins have the essential function of forming T-loops at the ends of chromosomes, which protect telomeres by preventing them from being recognized as DNA damage by DNA Polymerase. However, this also has the negative effect of making it impossible for DNA polymerase to repair telomeric damage [1]. Therefore, addressing this hallmark may require both extending telomeres and developing a way to repair DNA damage in telomeres.
· Epigenetic alterations: Epigenetics are modifications that do not change the DNA sequence, but instead turn genes “on” and “off”. There are several epigenetic mechanisms potentially at work during the aging process, such as DNA methylation, histone modifications, and chromatin remodeling. Reversing these epigenetic changes appears to ameliorate some of the effects of aging and even extend life-span in mice. The role of epigenetics in aging is exemplified by the epigenetic enzyme SIRT6, which extends longevity in mice when activated [1]. Epigenetic aging clocks, such as the Horvath clock have been proposed as biomarkers of aging progression, and have been used to determine the effectiveness of anti-aging interventions [2].
· Loss of proteostasis: Proteostasis refers to protein homeostasis, which is the maintenance of stable functional proteins. During aging, proteostasis diminishes and the mechanisms that prevent or repair misfolded proteins, as well as those that remove misfolded proteins (proteolytics) become impaired. Loss of proteostasis causes aggregates of misfolded proteins, which are implicated in Alzheimer’s, Parkinson’s and cataracts [1].
· Deregulated nutrient sensing: Decreased nutrient sensing occurs with increased physiological aging. This may be an adaptive mechanism by cells to reduce metabolism, thereby reducing cellular damage and extending lifespan as we age. Although decreased nutrient signaling can extend lifespan, it can also be lethal to cells at very low levels, which can aggravate aging. Thus, a balance is needed to extend healthy lifespan. There are four nutrient sensing pathways: Insulin and IGF-1 signaling (IIS), mechanistic target of rapamycin (mTOR), AMP-activated protein kinase (AMPk), and sirtuins. The IIS and mTOR pathways signal nutrient abundance, so downregulating them extends lifespan by decreasing cell growth and anabolic metabolism. Conversely, the AMPk and sirtuin pathways signal nutrient scarcity, so their upregulation extends lifespan by decreasing nutrient sensing, thereby mimicking dietary restriction. There are side-effects to upregulating and deregulating some of these nutrient signaling pathways, such as impaired wound healing, insulin resistance, cataract formation, and testicular degeneration when the mTOR pathway is downregulated by rapamycin administration [1]. Therefore we must proceed cautiously when making adjustments to nutrient sensing.
· Mitochondrial dysfunction: Mitochondrial dysfunction refers to mitochondrial degeneration and reduced mitochondrial bioenergetics efficiency. Mitochondrial biogenesis, meaning the increase in the mass of mitochondria, decreases with aging, and damaged mitochondria persist because the ability to remove damaged mitochondria also diminishes with aging. High levels of reactive oxygen species (ROS) can cause damage to mitochondria. Repairing or replacing dysfunctional mitochondria should be beneficial to health span, since we know that mitochondrial dysfunction accelerates aging in mammals [1].
· Cellular senescence: Cellular senescence refers to cells which have entered a state of arrested growth in response to cellular damage. In other words, senescent cells lose functionality and no longer undergo cellular division. Cells become senescent due to telomere shortening, DNA damage, and activation of the INK4a/ARF locus. Senescent cells cause increases in inflammation, which can aggravate aging. Since senescent cells accumulate with age, addressing this hallmark may require preventing the damage that causes senescence as well as improving the body’s capacity to efficiently remove senescent cells. In addition, progenitor cells will need to be able to repopulate tissues with new cells to replace the removed senescent cells [1].
· Stem-cell exhaustion: Stem-cell exhaustion refers to stem cells and progenitor cells accumulating damage over time, and eventually becoming depleted with age. Stem cells and progenitor cells are necessary to maintain functionality of our organs by replacing and repairing damaged cells [1]. Improving stem cell function and replacing depleted stem cells is thus a very promising area of research aimed at improving the regenerative capacity of the body.
· Altered intercellular communication: Aging causes changes in cell-cell signaling at all levels. Neuronal and hormonal signaling become deregulated, resulting in increased inflammation (inflammaging), decreased immune function (immunosenescence), and changes in the extracellular environment. It may be possible to reduce some of the effects of aging by improving cell communication with blood-borne factors and anti-inflammatory agents [1].
Conclusion
Scientists and aging researchers have garnered a great deal of knowledge regarding the biological mechanisms of aging in recent years. However, there is still much to learn about the drivers of aging, especially in regards to how the nine hallmarks of aging affect one another. The more we know about the biology of aging, the easier it will be to develop therapies that target the specific causes of aging. With the knowledge we have, scientists at universities and in the private sector are already at work developing potential treatments for aging.
Interested in learning about research on potential treatments for aging? Find my next article here. Missed my first article on why aging should be a priority? Find that here.
References:
[1] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194–1217. https://doi.org/10.1016/j.cell.2013.05.039
[2] Raj, K., & Horvath, S. (2020). Current perspectives on the cellular and molecular features of epigenetic ageing. Experimental Biology and Medicine. https://doi.org/10.1177/1535370220918329
[3] Bernardes de Jesus, B., Vera, E., Schneeberger, K., Tejera, A. M., Ayuso, E., Bosch, F., & Blasco, M. A. (2012). Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. EMBO molecular medicine, 4(8), 691–704. https://doi.org/10.1002/emmm.201200245
