Vitamin D deficiency accelerates ageing and age‐related diseases: a novel hypothesis (2024)

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J Physiol. 2017 Nov 15; 595(22): 6825–6836.

Published online 2017 Oct 31. doi:10.1113/JP274887

PMCID: PMC5685827

PMID: 28949008

Michael J. Berridge^1,*

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Abstract

Ageing can occur at different rates, but what controls this variable rate is unknown. Here I have developed a hypothesis that vitamin D may act to control the rate of ageing. The basis of this hypothesis emerged from studyng the various cellular processes that control ageing. These processes such as autophagy, mitochondrial dysfunction, inflammation, oxidative stress, epigenetic changes, DNA disorders and alterations in Ca²⁺ and reactive oxygen species (ROS) signalling are all known to be regulated by vitamin D. The activity of these processes will be enhanced in individuals that are deficient in vitamin D. Not only will this increase the rate of ageing, but it will also increase the probability of developing age‐related diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis and cardiovascular disease. In individual with normal vitamin D levels, these ageing‐related processes will occur at lower rates resulting in a reduced rate of ageing and enhanced protection against these age‐related diseases.

Keywords: autophagy, mitochondrial dysfunction, inflammation, oxidative stress, epigenetics, DNA disorders, calcium, reactive oxygen species (ROS), Vitamin D

Autophagy and ageing

There is increasing evidence that autophagy plays a key role in maintaining healthy ageing (Rubinsztein etal. 2011; Madeo etal. 2015; Plaza‐Zabala etal. 2017). In those families that have extended longevity, the process of autophagy is better maintained (Raz etal. 2017). Autophagy is an essential process in that it maintains healthy cells by removing damaged proteins and malfunctioning organelles, especially the mitochondria (Hubbard etal. 2012; Fivenson etal. 2017; Palikaras etal. 2017). As mitochondria age, there is a decline in their ability to generate ATP and they begin to generate large amounts of reactive oxygen species (ROS). Such an increase in oxidative stress is one of the processes that enhances ageing (Fig.1; Terman etal. 2007; Salminen etal. 2012; Ureshino etal. 2014). Therefore, to reduce ageing it is essential that these damaged mitochondria are removed by autophagy. It is essential, therefore, that the process of autophagy is maintained and there is evidence that it may decline when ageing is occurring at a fast rate.

The autophagy process is regulated by changes in the level of Ca²⁺ (Høyer‐Hansen etal. 2007; Decuypere etal. 2011b; La Rovere etal. 2016; Sun etal. 2016; Luyten etal. 2017) and by increases in the levels of ROS (Navarro‐Yepes etal. 2014). The action of Ca²⁺ is complicated because it exerts a dual action on autophagy. For example, an increase in the level of Ca²⁺, especially following the activation of inositol trisphosphate receptors (InsP₃Rs), acts to inhibit autophagy (Criollo etal. 2007). On the other hand, a reduction in the level of Ca²⁺ also enhances autophagy. It has been proposed that the nature of the cellular state may determine how this dual action of Ca²⁺ occurs (Decuypere etal. 2011b).

There is now growing evidence that vitamin D plays an important role in maintaining autophagy (Fig.1; Yuk etal. 2009; Høyer‐Hansen etal. 2010; Verway etal. 2010; Wu & Sun, 2011; Jang etal. 2014; Uberti etal. 2014; Wang etal. 2016; Chirumbolo etal. 2017; Mushegian, 2017; Tavera‐Mendoza etal. 2017; Wei etal. 2017). It is possible that vitamin D will act to promote autophagy by regulating the level of Ca²⁺ through its ability to promote the expression of Ca²⁺ pumps and Ca²⁺ buffers as will be described in a later section. By maintaining autophagy, vitamin D will reduce the ageing process by ensuring that the mitochondria do not generate excessive amounts of ROS, which have been implicated in ageing as described below.

Inflammation and ageing

Inflammation has been implicated in the process of ageing (Cevenini etal. 2010, 2013; Salminen etal. 2012; López‐Otín etal. 2013; Petersen & Smith, 2016; Di Benedetto etal. 2017). Damaged mitochondria may play a role in initiating this increase in inflammation (Green etal. 2011). These dysfunctional mitochondria are the result of a decline in autophagy that acts normally to remove such damaged mitochondria as described above (Salminen etal. 2012).

One of the important actions of vitamin D is to reduce inflammation (Fig.1; Garcion etal. 1999; Hewison, 2010; Sundar & Rahman, 2011; Briones & Darwish 2012; Berk etal. 2013; Alvarez etal. 2014; Lucas etal. 2014; Wang etal. 2014). One way it does this is to reduce the expression of inflammatory cytokines (d'Hellencourt etal. 2003; Beilfuss etal. 2012; Grossmann etal. 2012; Wei & Christakos, 2015), which are such a prominent feature of how inflammatory responses alter cellular activity. One of these inflammatory cytokines is tumour necrosis factor‐α (TNF‐α), which acts to increase the expression of the InsP₃Rs (Park etal. 2009) thus inducing an increase in the level of Ca²⁺, which accelerates ageing as described below.

Mitochondrial dysfunction and ageing

Mitochondrial dysfunction is one of the main drivers of ageing (Lin & Beal 2006; Petrosillo etal. 2008; Wang etal. 2013; Yin etal. 2016). As a result of their dysfunction, the mitochondria produce insufficient ATP but generate increased amounts of ROS that enhance oxidative stress (Terman etal. 2006, 2010; Petrosillo etal. 2008; Toman & Fiskum, 2011; Marzetti etal. 2013; Wang etal. 2013), which is one of the main drivers of ageing (Fig.1). It is likely that this mitochondrial dysfunction is driven by a deficiency in vitamin D.

One of the main functions of vitamin D is to maintain the activity of the mitochondrial respiratory chain (Consiglio etal. 2015). Vitamin D also regulates the expression of the uncoupling protein (UCP), which is located on the inner mitochondrial membrane where it acts to control thermogenesis (Abbas, 2016). During vitamin D deficiency, mitochondrial respiration declines due to a reduction in the nuclear mRNA molecules and proteins that contribute to mitochondrial respiration (Kim etal. 2014; Scaini etal. 2016). In particular, the formation of ATP declines because there is a vitamin D‐dependent reduction in the expression of complex I of the electron transport chain. This decline in the electron transport chain also results in an increase in the formation of ROS, which induce oxidative stress, which is a feature of ageing (Brownlee, 2005; Lowell & Shulman, 2005) as described in the following section.

Members of the sirtuin family, such as sirtuin (SIRT) 1, also play an important role in maintaining normal mitochondrial function (Westphal etal. 2007). The sirtuins, which are NAD⁺‐dependent protein deacetylases, function as anti‐ageing proteins that reduce ageing by regulating a wide range of protein targets (Guarente, 2007; Law etal. 2009; Donmez & Guarente, 2010; Grabowska etal. 2017). The sirtuins also play an important role in reducing brain ageing (Satoh etal. 2017). SIRT1 contributes to mitochondrial biogenesis by activating PGC‐1α. These beneficial effects of SIRT1 on mitochondrial function are regulated by vitamin D, which acts by increasing the formation of SIRT1 (An etal. 2010; Polidoro etal. 2013; Chang & Kim, 2016; Marampon etal. 2016; Manna etal. 2017).

One of the main actions of vitamin D is to maintain the normal mitochondrial control of cellular bioenergetics (Calton etal. 2015). The Ca²⁺ buffering role of dysfunctional mitochondria is also compromised resulting in an increase in the intracellular level of Ca²⁺, which is a feature of ageing as described later.

Oxidative stress and ageing

Oxidative stress, which is one of the main drivers of ageing (Finkel & Holbrook, 2000; Stadtman, 2002; Brewer, 2010; Paradies etal. 2011; Ureshino etal. 2014; Petersen & Smith, 2016), is caused by the increase in ROS formation by dysregulated mitochondria as described above. Vitamin D plays a major role in regulating ROS levels through its ability to control the expression of cellular antioxidants as part of its role to maintain phenotypic stability of cell signalling pathways (Dong etal. 2012; George etal. 2012; Berridge, 2015a,b). Vitamin D also supports such redox control by maintaining normal mitochondrial function (Bouillon & Verstuyf, 2013; Ryan etal. 2016) as described earlier.

Many of the genes that are controlled by the vitamin D–Klotho–Nrf2 regulatory network function to maintain redox homeostasis. For example, vitamin D together with Klotho and Nrf2 increases cellular antioxidants to maintain the normal reducing environment within the cell thereby preventing oxidative stress by removing ROS. For example, the expression of γ‐glutamyl transpeptidase, glutamate cysteine ligase and glutathione reductase, which contribute to the synthesis of the major redox buffer glutathione (GSH), is regulated by vitamin D. VitaminD also increases the activity of glucose‐6‐phosphate dehydrogenase to increase the formation of GSH. It down‐regulates the nitrogen oxide (NOX) that generates ROS while upregulating the superoxide dismutase that rapidly converts O₂^−• to H₂O₂ (Berridge, 2016). Vitamin D also up‐regulates expression of the glutathione peroxidase that drives the conversion of H₂O₂ to water.

Ca²⁺ signalling and ageing

An alteration in the Ca²⁺ signalling pathway has also be linked to an acceleration in the process of ageing (Fig.1; Mattson, 2007; Puzianowska‐Kuznicka & Kuznicki 2009; Ureshino etal. 2010; Decuypere etal. 2011a; Gant etal. 2014; Berridge, 2016; Veldurthy etal. 2016; Martin & Bernard, 2017). During ageing, there is an alteration in Ca²⁺ signalling in atrial myocytes (Herraiz‐Martínez etal. 2015) and neurons (Buchholz etal. 2007; Murchison & Griffith, 2007). The relationship between Ca²⁺ signalling and ageing is particularly evident in the ageing brain (Thibault etal. 2001; Foster & Kumar, 2002; Gant etal. 2006; Foster, 2007; Thibault etal. 2007; Kumar etal. 2009; Gant etal. 2014). An increase in the release of Ca²⁺ from internal stores by the InsP₃Rs and ryanodine receptors (RYRs) contributes to this increase in neural Ca²⁺ levels during ageing (Banerjee & Hasan, 2005; Puzianowska‐Kuznicka & Kuznicki, 2009; Santulli & Marks 2015). The increase in Ca²⁺ release from the RYRs is caused by a decline in the expression of the FK506‐binding proteins 1a and 1b (FKBP1a/1b), which act normally to reduce the release of Ca²⁺ by the RYRs (Gant etal. 2014). Inserting an adeno‐associated viral vector bearing a transgene encoding FKBP1b was able to reduce the effects of the elevated levels of Ca²⁺ that function to impair cognitive functions that occur during ageing (Gant etal. 2015).

When considering the role of Ca²⁺ in ageing, it is important to include magnesium, which is closely linked to both vitamin D and Ca²⁺. One the functions of magnesium is to enhance the synthesis of vitamin D (Rude etal. 1985; Risco & Traba, 1992; Deng etal. 2013). There are now indications that low levels of magnesium are linked to a number of diseases that are also associated with vitamin D deficiency. For example, a deficieny in magnesium has been linked to ageing. Lower magnesium levels have been found in individuals with hypertension and metabolic syndrome (Rotter etal. 2015). Low blood pressure and an increased risk of stroke have also been observed in individual with low magnesium levels (Bain etal. 2015). Some of the actions of magnesium are mediated through a reduction in Ca²⁺ signalling processes. In the brain, extracacellular magnesium can reduce Ca²⁺ entry through voltage‐gated Ca²⁺ channels and NMDA receptors (Wilmott & Thompson 2013). An increase in magnesium in the brain reverses the decline in cognition in Alzheimer's disease (Li etal. 2014). It is clear from all this evidence that magnesium plays an important role in regulating the activity of both Ca²⁺ and vitamin D.

During ageing, there is a decline in the level of the Ca²⁺ buffer calbindin‐D_28K in the cholinergic neurons in the brain (Riascos etal. 2011). In motoneurons, vitamin D acts to increase the expression of calbindin‐D28 and parvalbumin (Alexianu etal. 1998). High levels of these buffers contributes to the low levels of Ca²⁺. A decline in these buffers, caused by a decline in the level of vitamin D that occurs during ageing, will result in an elevation of the level of Ca²⁺, which is a feature of brain ageing. In the ageing brain, there also is a decrease in the expression of Bcl‐2 (Ureshino etal. 2010), which may contribute to the increase in Ca²⁺ release by the InsP₃Rs. Bcl‐2 interacts with the InsP₃Rs to reduce the release of Ca²⁺ (Distelhorst & Bootman 2011). One of the consequences of this increase in the levels of Ca²⁺ during brain ageing is a decline in cognition (Thibault etal. 2001, 2007; Foster 2007; Toescu & Verkhratsky, 2007; Toepper, 2017). This decline in cognition is particularly evident in ageing patients (Seamans etal. 2010). In addition to this decline in cognition, there also is evidence of a decline in sleep in older adults, which may contribute to the decline in cognition (Mander etal. 2017).

Vitamin D has been shown to alleviate this enhanced Ca²⁺ elevation in the ageing brain. By reducing the levels of Ca²⁺, vitamin D restores normal cognitive function (Landfield & Cadwallader‐Neal, 1998; Brewer etal. 2006; Przybelski & Binkley, 2007; Perna etal. 2014; Schlögl & Holick, 2014; Toffanello etal. 2014; Banerjee et al. 2015). Strong support for such a notion has come from the study of the decline in cognition in ageing rats that is driven by a marked increase in the amplitude of the slow after‐hyperpolarization (sAHP) that depends on a build‐up of Ca²⁺ that activates the SK potassium channel (Landfield, 1987). This Ca²⁺ signal, which depends on the opening of L‐type voltage‐dependent Ca²⁺ channels that provides trigger Ca²⁺ to activate RYRs, inhibits memory by curtailing the spiking activity necessary for LTP, whereas the increase in Ca²⁺ stimulates calcineurin to induce the long‐term depolarization that erases memories. The development of this sAHP during ageing depends on dysregulation of both Ca²⁺ and ROS signalling that can be directly attributed to vitamin D deficiency.

One of the consequences of the elevation of Ca²⁺ and ROS that occurs during vitamin D deficiency is an increase in the incidence of age‐related diseases. For example, the onset of Alzheimer's disease occurs in those individuals who are deficient in vitamin D (Banerjee etal. 2015) and thus have abnormally elevated levels of both Ca²⁺ and ROS, which may induce the formation of the pathological amyloid beta (Aβ) oligomers that then initiate the onset of Alzheimer's disease (Berridge, 2016). Such a possibility is based on the fact that elevated levels of Ca²⁺ act to stimulate the enzymes that form Aβ (Querfurth & Selkoe, 1994; Green & LaFerla, 2008; Itkin etal. 2011). Such an increase in Ca²⁺ that occurs during vitamin D deficiency may also be associated with the onset of other neurodegenerative diseases such as Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis.

Vitamin D acts to increase the expression of both Klotho and Nrf2, which also act to reduce the ageing process. Vitamin D working together with Nrf2 and Klotho plays an essential role in maintaining the phenotypic stability of many cell signalling pathways and particularly the Ca²⁺ and redox signalling systems (Berridge, 2015a, b). This vitamin D–Klotho–Nrf2 regulatory system can prevent the dysregulation of Ca²⁺ and ROS signalling through multiple mechanisms. Vitamin D suppress the expression of the L‐type Ca²⁺ channel (Brewer etal. 2001, 2006) that initiates the Ca²⁺ signal that induces the sAHP and it also maintains the expression of plasma membrane Ca²⁺‐ATPase (PMCA) and the Na⁺/Ca²⁺ exchanger (NCX1), which extrude Ca²⁺ from the cell. In dendritic cells, vitamin D reduces the level of Ca²⁺ by increasing the expression of the NCX1 that extrudes Ca²⁺ from the cell (Shumilina etal. 2010). Klotho, which is an anti‐ageing protein (Kim etal. 2015), acts to stimulate the Na⁺/K⁺‐ATPase responsible for maintaining the Na⁺ gradient necessary for Ca²⁺ extrusion by NCX1. Finally, premature ageing occurs when Nrf2 is repressed (Kubben etal. 2016). Nrf2 increases the expression of many antioxidants that ensure that ROS levels are kept low (Lewis etal. 2010; Niture etal. 2010; Sykiotis etal. 2011; Nakai etal. 2014), which will prevent the sensitization of the RYRs that are triggering the sAHP and memory erasure.

The central role of vitamin D deficiency in this neuronal dysregulation and cognitive decline can be reversed by treating neurons with vitamin D, which dramatically reduces the sAHP (Brewer etal. 2006). When tested on ageing rats, vitamin D was found to enhance hippocampal synaptic function and, more significantly, it could prevent the decline in cognition (Landfield & Cadwallader‐Neal, 1998; Latimer etal. 2014).

Epigenetics and ageing

Epigenetic changes in the genome play an important role in the ageing process (Gonzalo, 2010; Gravina & Vijg, 2010; Ford etal. 2011; Lillycrop etal. 2014; Benayoun etal. 2015; Aunan etal. 2016; Pal & Tyler, 2016; Sen etal. 2016). The main epigenetic change that influences ageing is DNA and histone methylation, which has a marked influence on expression of many of the genes that are responsible for healthy ageing. A good example of this is the fact that such epigenetic changes have been linked to oxidative stress (Hedman etal. 2016). As described earlier, such oxidative stress is enhanced by a decline in the expression of cellular antioxidants. Such a view is supported by the fact that the most important signalling pathways that are maintained by vitamin D are the Ca²⁺ and redox signalling pathways (Berridge, 2016).

One of the major regulators of antioxidant expression is vitamin D and there is increasing evidence that vitamin D also controls the epigenetic landscape of its multiple gene promoters (Hossein‐nezhad & Holick, 2012; Hossein‐nezhad & Holick, 2013; Fetahu etal. 2014; Xue etal. 2016). Both the acetylation and methylation states of its promotor regions are maintained by vitamin D. With regard to acetylation, the vitamin D receptor (VDR) complex recruits histone acetylases such as p300–CREB‐binding protein (CBP) and steroid receptor coactivator 1 (SRC‐1). Perhaps its most significant action is to increase the expression of a number of DNA demethylases. Control of demethylation is critical because many of the genes regulated by vitamin D are silenced by methylation of the CpG islands located in their promotor regions. Such hypermethylation can also account for a decline in the expression of Klotho that occurs during ageing (King etal. 2011). Such age‐dependent hypermethylation is also evident in many age‐related diseases (cancer, cardiovascular and neurodegenerative diseases; van Otterdijk etal. 2013). For example, hypermethylation of promotors in GABAergic neurons may contribute to the phenotypic remodelling responsible for schizophrenia and bipolar disorder (Guidotti etal. 2011). Since many of these diseases have also been linked to vitamin D deficiency, it is not surprising to find that vitamin D can modulate the epigenetic landscape. Vitamin D controls the expression of a number of key DNA demethylases such as Jumonji C domain‐containing demethylase (JMJD) 1A, JMJD3, lysine‐specific demethylase (LSD) 1 and LSD2 (Pereira etal. 2012), which contributes to its ability to maintain phenotypic stability.

DNA disorders and ageing

Two DNA disorders contribute to the ageing process: telomere shortening and DNA alterations caused by the defective repair of DNA double‐strand breaks (DSB); both cause genomic instability (Ding & Shen, 2008; Gonzalez‐Suarez etal. 2011; López‐Otín etal. 2013; Chow & Herrup, 2015; Aunan etal. 2016). It is of interest that both these defects can be reduced by vitamin D. Telomeres, which are located at the ends of chromosomes, play an important role in preventing the ends of chromosomes from fusing with neighbouring chromosomes (Campisi etal. 2001; Oeseburg etal. 2010; Prasad etal. 2017). During ageing, there is a decline in the length of these telomeres and this causes a decline in cell proliferation resulting in cell senescence, which characterizes the ageing processes (Prasad etal. 2017). There is increasing evidence that vitamin D can act to reduce the rate of telomere shortening (Hoff*cker etal. 2013; Liu etal. 2013; Pusceddu etal. 2015; Beilfuss etal. 2017; Mazidi etal. 2017). SIRT6 can also play an important role in stabilizing both the genome and telomeres (Tennen & Chua, 2011).

The defective repair of DNA double‐strand breaks (DSBs) is another DNA disorder that contributes to ageing. A deficiency of p53‐binding protein 1 (53BP1), which is a key factor in DNA DSBs, is the cause of the defective DSB. It has been established that the cysteine protease cathepsin L (CTSL) is responsible for degrading 53BP1 (Gonzalez‐Suarez etal. 2011; Grotsky etal. 2013). Vitamin D acts to prevent this DNA disorder caused by DSBs by inhibiting CTSL, which leads to the stabilizatioin of 53BP1 (Gonzalez‐Suarez etal. 2011; Grotsky etal. 2013).

Conclusion

There is increasing evidence that ageing can proceed at variable rates. In this review, I have developed the hypothesis that vitamin D may play a major role in regulating the rate of ageing. The basis of this hypothesis is that a number of the processes that drive ageing (e.g. autophagy, mitochondrial dysfunction, inflammation, oxidative stress, epigenetics, DNA disorders, and alterations in Ca²⁺ and ROS signalling) are regulated by vitamin D. Normal levels of vitamin D are capable of maintaining these processes at their normal low rates and this slows down the ageing process and also helps to prevent the onset of a number of age‐related diseases (e.g. Alzheimer's disease, Parkinson's disease, multiple sclerosis, hypertension and cardiovascular disease).

When vitamin D is deficient, there is an increase in the activity of these ageing processes that not only accelerates the rate of ageing, but it also creates the conditions that initiate the onset of the age‐related diseases such as Alzheimer's disease. Such an increase in Ca²⁺ that occurs during vitamin D deficiency has also been associated with the onset of other neurodegenerative diseases such as Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis.

Additional information

Competing interests

There are no competing interests.

Biography

•

Michael J. Berridge is best known for his discovery of inositol trisphosphate (IP₃), which plays a universal role in regulating many different cellular processes. He became a Fellow of Trinity College in 1972 and was elected a Fellow of The Royal Society in 1984. For his work on second messengers he has received numerous awards and prizes, including The King Faisal International Prize in Science, The Louis Jeantet Prize in Medicine, The Albert Lasker Medical Research Award, The Heineken Prize, the Shaw Prize, and The Wolf Foundation Prize in Medicine. In 1998 he was knighted for his service to science.

Notes

This is an Editor's Choice article from the 15 November 2017 issue.

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