Multiple studies have reported the changes of PC contents as animal ages, with species and tissue specificity. For example, it was reported that the contents of most PCs are notably decreased in the aged nematodes (Gao et al., 2017; Wan et al., 2019). Additionally, the overall PC contents show a significant reduction in the kidney of aged mouse (Braun et al., 2016), while the accumulation of PCs has been detected in the hippocampus of a brain aging mice model (Lin et al., 2016). In line with this, major mitochondrial PC species are found to be increased in the brain of aged humans (Hancock et al., 2015, 2017). Thus, the reduction of overall PC contents appears to be a general feature of animal aging, except for the aged brain where the PC contents seem to be increased. Studies in long-lived organisms further support this idea, as overall PC contents are greater in multiple tissues of the long-lived naked mole-rat compared with that of mice (Mitchell et al., 2007). It is also the case for humans, as most PC species are higher in the centenarians than that in the elderly (Montoliu et al., 2014).

More intriguingly, besides the accumulation of overall PC contents, the long-lived centenarians have a unique metabolic signature of PC, showing that several specific PC species are unexpectedly decreased (Collino et al., 2013). These decreased PCs remain similar between the centenarians and young people, while elevating in the elderly (Collino et al., 2013), thus may representing a youth or longevity signature. A study in model organism C. elegans also shows that certain PCs, mainly some unsaturated ones, remain at low levels in long-lived mutants regardless of age (Wan et al., 2019). The long-lived naked mole rats also have low levels of PCs that contain unsaturated docosahexaenoic acid (DHA, 22:6) as acyl chains, compared with mice. As such, we propose that specific PCs, most likely some unsaturated ones, are negatively associated with animal longevity.

It seems that the overall PC contents and specific PCs are associated with the age difference. In C. elegans, a Dietary supplement of PC mixture can significantly extend the lifespan and improve the healthspan of nematodes via the longevity transcription factor DAF-16 (Kim et al., 2019), which is consistent with the idea that the decline of total PCs is not only a biomarker of aging but also a reason for it. The mechanism underlying the total PCs effects on lifespan is currently not clear but may be related to membrane fluidity. The decline of total PCs can cause membrane stiffening (Dawaliby et al., 2016) that is observed in aged cells and animals (Yu et al., 1992; Levi et al., 1997). Moreover, this age-associated decline of membrane fluidity can be reversed by longevity-inducing interventions like dietary restriction (Yu et al., 1992).

Unsaturated PC species may act differently with total PCs in the context of lifespan regulation. A recent C. elegans study reported that the levels of unsaturated PCs are decreased in a long-lived C. elegans model. More importantly, the reduction of unsaturated PC species likely function in the endoplasmic reticulum (ER) to promote longevity by activating the ER-resident calcium channel, downstream calcium-sensitive kinases, and the transcription factor DAF-16 (He et al., 2021), suggesting that specific unsaturated PCs may interact with membrane proteins to regulate longevity. The finding that reduction of unsaturated PC is beneficial for lifespan extension is consistent with the idea that low contents of unsaturated PCs may be a longevity signature. Understanding how the changes of certain unsaturated PCs determine lifespan deserves further investigation.

Aging is a complex process associated with the functional decline of essential organs and tissues, thus representing a major risk factor for many chronic diseases referred to as aging-related diseases. As PCs accumulate in the brain of aged animals (Hancock et al., 2015, 2017), studies also pay attention to the function of PCs in neurodegenerative diseases such as Alzheimer’s disease (AD). In patients with AD, the contents of unsaturated PC 36:5 and PC 38:6 are lower in the plasma and are correlated with hippocampus atrophy (Kim et al., 2017). Consistently, the higher contents of several unsaturated PCs are associated with a slower decline in AD-related cognition (Li et al., 2019). By contrast, the accumulation of PC-O (16:0/2:0) is found to associate with multiple AD pathologies, such as the aggravated tau pathology, enhanced vesicular release, and signaling neuronal loss (Bennett et al., 2013). Thus, it appears that certain unsaturated PCs are critical for the functional maintenance of neurons.

It is not fully understood how certain PCs maintain neuronal function and protect against neurodegenerative diseases. A key and common pathology of neurodegenerative diseases is protein aggregation. The ER is critical for protein folding. when misfolded proteins accumulate in the ER (also known as ER stress), ER unfolded protein response is induced to assist protein folding and maintain cellular proteostasis. Indeed, PC disturbance has been linked to abnormal ER function and protein aggregation (O’Leary et al., 2018; Kumar et al., 2019; Shyu et al., 2019). As a consequence, PC disturbance is recognized as a stress to the ER and can promote the ER UPR (Volmer et al., 2013; Halbleib et al., 2017; Ho et al., 2020). A recent study of C. elegans also supports the crucial of certain PCs in ER homeostasis. The contents of unsaturated PC are increased in the somatic cells of C. elegans upon DNA damage, which represents an aging risk factor. Moreover, the elevation of unsaturated PCs is critical for promoting the ER UPR without causing ER stress, thus enhancing cellular maintenance (Deng et al., 2021). Intriguingly, the neurons and C. elegans somatic cells share some common features, as they are both postmitotic cells that cannot proliferate and are irreplaceable. In this regard, we propose that certain unsaturated PC species may be of great importance for the functional maintenance of postmitotic cells such as neurons during the aging process.

Phosphatidylethanolamine is the second abundant PL in organisms. Emerging pieces of evidence show that PE contents also change with age. Major PE species decrease significantly in the aged nematodes (Gao et al., 2017), as well as in the brain and kidney of old mice (Braun et al., 2016; Lin et al., 2016), suggesting that PE reduction may also be a general feature of aging. Moreover, a human lipidomic study has found that the contents of ether lipid derived from PE are lower in the centenarians compared with that in the elderly people (Pradas et al., 2019), suggesting this specific form of PE may function as a centenarian signature that may promote longevity. Interestingly, although the contents of overall mitochondrial PE in the brains of the elderly are reduced, mitochondrial PEs containing unsaturated docosahexaenoic acid (DHA, 22:6) were found to be increased significantly (Hancock et al., 2015, 2017). Due to the importance of DHA for neuronal development and function, the increase in DHA-containing PEs with age may be an adaptive and protective mechanism for brain aging, suggesting specific PE species and overall PE contents may affect health during aging differentially.

Studies has shown that the increase of PE contents, either by dietary supplementation of PE precursor ethanolamine or by the overexpression of PE-biosynthetic enzymes phosphatidylserine decarboxylases (PSD), extends lifespan in model organisms of yeast, fly, and mammals (Rockenfeller et al., 2015). And the lifespan extension effects of PE are associated with increased autophagic flux (Rockenfeller et al., 2015), a positive lifespan regulator in many model organisms (Hansen et al., 2018), suggesting PE supplementation may increase lifespan by promoting autophagy.

In contrast, the reduction of PE by suppressing PSD causes ROS production and accelerates aging in yeast (Rockenfeller et al., 2015). The relationship between PE and ROS is also supported by a C. elegans study that supplementation of PE enhances the resistance to oxidative stress and promotes longevity via DAF-16 (Park et al., 2021). These findings suggest that PE plays pivotal roles in life extension, likely acting as a regulator of ROS production. ROS is a byproduct of mitochondrial respiration and is generally associated with mitochondrial defects or dysfunction. Indeed, PSD-mediated PE production occurs in the mitochondrial inner membrane and is found to be essential for the activity of the electron transport chain (Calzada et al., 2019). Accordingly, PSD knockdown compromised the mitochondrial integrity and muscle mass in the mice (Selathurai et al., 2019). Thus, it is conceivable that mitochondria activity is key for lifespan determination in response to PE alteration.

Cardiolipin is a symbolic phospholipid of the mitochondrial membrane. CL plays a critical role in many aspects of the mitochondrial function: stabilizes respiratory chain supercomplex, regulates the activity of mitochondrial membrane proteins, and controls essential mitochondrial signaling pathways (Pfeiffer et al., 2003; Dudek, 2017). Due to the special location, CL is closely related to respiration as well as a normal function of the respiratory chain complex, which leads to its association with aging and age-related disease (Shi, 2010; Paradies et al., 2011; Hsu and Shi, 2017). Consistently, CL contents were found to be decreased in the aged nematodes and rodents (Gao et al., 2017; Šmidák et al., 2017), while the contents of CL are notably increased in the adipose tissues of long-lived model Ames dwarf mice compared with normal mice (Darcy et al., 2020), suggesting the idea that increased CLs are beneficial for health and longevity. Indeed, a yeast study shows that perturbation of CL synthesis leads to decreased longevity (Zhou et al., 2009).

Notably, CLs are highly sensitive to oxidative stress and the peroxidation of CLs can cause damage to the respiratory chain complex, which in turn causes mitochondrial defects and respiratory dysfunction. In line with this, the contents of total CLs were found to decrease, while the peroxidized CLs are significantly increased in the brains of aged rats, which is associated with impaired activity of brain mitochondrial respiratory complex I (Petrosillo et al., 2008). The peroxidation of CLs is influenced by the CL remodeling, a process catalyzed by the acyltransferase (ALCAT1) that synthesizes CLs from lysocardiolipin (Cao et al., 2004). The resynthesized CLs are highly sensitive to oxidative damage by ROS due to the enriched double bonds in poly-unsaturated acyl chains. Thus, the pathological CL remodeling can exacerbate oxidative stress as well as mitochondrial dysfunction (Li et al., 2010, 2012), while the inhibition of CL remodeling may improve the aging-associated functional decline of mitochondria. Indeed, ALCAT1 inhibition or deficiency could improve mitochondrial function, alleviate oxidative stress and prevent disease progression in the context of many aging-related diseases including obesity, Parkinson’s disease, aging-related heart disease, and non-alcoholic fatty liver disease (Li et al., 2010; Liu et al., 2012; Wang et al., 2015; Song et al., 2019). These findings link ALCAT1 to mitochondrial dysfunction and reveal a critical role for CL remodeling in age-related diseases. A balance between the non-peroxidized CLs and peroxidized CLs is crucial for maintaining mitochondrial function and enabling healthy aging.