Eto and Higuchi ﻿
Journal of Physiological Anthropology(2023) 42:11
https://doi.org/10.1186/s40101-023-00328-1

Journal of
Physiological Anthropology

Open Access

REVIEW

Review on age‑related differencesin non‑visual effects of light: melatonin
suppression, circadian phase shift and pupillary
light reflex in children to older adults
Taisuke Eto1,2   and Shigekazu Higuchi3*   

Abstract
Physiological effects of light exposure in humans are diverse. Among them, the circadian rhythm phase shift effectin order to maintain a 24-h cycle of the biological clock is referred to as non-visual effects of light collectively withmelatonin suppression and pupillary light reflex. The non-visual effects of light may differ depending on age, andclarifying age-related differences in the non-visual effects of light is important for providing appropriate light environments for people of different ages. Therefore, in various research fields, including physiological anthropology, manystudies on the effects of age on non-visual functions have been carried out in older people, children and adolescentsby comparing the effects with young adults. However, whether the non-visual effects of light vary depending on age
and, if so, what factors contribute to the differences have remained unclear. In this review, results of past and recent
studies on age-related differences in the non-visual effects of light are presented and discussed in order to provide
clues for answering the question of whether non-visual effects of light actually vary depending on age. Some studies,
especially studies focusing on older people, have shown age-related differences in non-visual functions including differences in melatonin suppression, circadian phase shift and pupillary light reflex, while other studies have shown nodifferences. Studies showing age-related differences in the non-visual effects of light have suspected senile constriction and crystalline lens opacity as factors contributing to the differences, while studies showing no age-related differences have suspected the presence of a compensatory mechanism. Some studies in children and adolescents haveshown that children’s non-visual functions may be highly sensitive to light, but the studies comparing with other age
groups seem to have been limited. In order to study age-related differences in non-visual effects in detail, comparative studies should be conducted using subjects having a wide range of ages and with as much control as possible forintensity, wavelength component, duration, circadian timing, illumination method of light exposure, and other factors(mydriasis or non-mydriasis, cataracts or not in the older adults, etc.).
Keywords Aging, Non-image forming effect, Older adults, Children, Light, Crystalline lens, Pupil, Melatonin, Circadianrhythm, Pupillary light reflex*Correspondence:
Shigekazu Higuchi
higu-s@design.kyushu-u.ac.jp
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Background
Many living organisms, including humans, have evolved
under sunlight, and information about the ambient environments that humans obtain through light and thephysiological responses induced by light in humans arediverse. The light that enters the eye, passes through thepupil and crystalline lens, and reaches the retina is processed by two major pathways in the brain to induce
physiological effects. The first is the visual effect that
occurs when light information reaches the visual cortex,
where it is processed to perceive brightness and color
vision. Light information converted to neural signals byclassical cones and rods is projected to the visual cortex via the thalamic lateral geniculate nucleus (LGN)
using the optic tract. The other is processed in the pathway where the neural signals directly reach the suprachiasmatic nucleus (SCN) in the hypothalamus via theretinohypothalamic tract (RHT), which causes physiological effects to synchronize the biological clock (circadianclock), such as sleep/wake rhythms with the 24-h light/
dark cycle associated with the earth’s rotation. Thesephysiological effects of light are called non-visual (ornon-image forming) effects, as distinguished from visual
effects, and include light-induced melatonin suppression
and pupillary light reflex in addition to the light entrainment effects of circadian rhythms.
Light performs a role as the strongest entrainment
factor for circadian rhythms. It has been shown thatbright light at night, such as artificial lighting, causes adelay and disruption of circadian rhythms and sleep [1]in both rural areas [2–4] and urban areas [5, 6], and isassociated with various health problems [7]. It has beenfound that circadian rhythm phases are advanced bycamp life without or with less access to artificial lighting in adults [8] and children [9]. These results suggestthat artificial lighting at night causes delay in circadianrhythms in humans in modern society. Various factors
have been shown to influence the non-visual effects oflight. For example, the non-visual effects of light havebeen found to vary with differences in intensity [10–12], wavelength [13–15], exposure duration [16–18],
and exposure circadian timing [19, 20]. The field ofphysiological anthropology, which focuses on environmental adaptability, also has a long history of researchon the non-visual effects in light environments [21].
Physiological anthropology has also focused on variations in physiological responses from the perspective ofenvironmental adaptability [22].
The non-visual effects of light are modulated not only
depending on light exposure conditions but also on factors on the human side. Recently, attention has been
paid to individual differences in non-visual responses tolight [23, 24]. While it has been reported that the nonvisual effects of light vary depending on genetics [25,26], season [27–29], ethnicity [30], and individual light
exposure history [31–33], the most commonly studied
factor is age [34]. In physiological anthropology, agerelated differences in the non-visual effects of light are
an important topic in terms of development [35] andaging [34]. Figure 1 shows that a conceptual scheme ofage-related differences in the non-visual effects of light.
This paper is a review of past studies and recent studies

Fig. 1 Conceptual scheme of age-related differences in non-visual effects of light (created with biorender.com)

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on age-related differences in light-induced melatonin
suppression, light entrainment of circadian rhythms,
and pupil light reflex.

suppression than the young adults when exposed to blue
light (456 nm) for 30 min. As for the reason for the significant age-related difference only for exposure to blue
light, Herljevic et al. mentioned the involvement of senile
constriction of the pupil and age-related opacity of thecrystalline lens. With aging, the pupil size diminishes [44,45] and the crystalline lens becomes opaque (decrease inlight transmittance) [46]. The decrease in light transmittance of the lens is particularly pronounced in the shortwavelength (blue) light range [47–49]. Figure 2 showsthat the crystalline lens transmittance spectra in vivo
measured by a Purkinje image-based system which wasdeveloped by authors [50] (depicted from data in Eto
2020 [50] and Eto 2021 [51]). As mentioned above, it
is known that ipRGCs are the main contributors to thenon-visual effects of light, including the melatonin suppression effects [52–54]. ipRGCs respond most strongly
to blue light around 480 nm among visible light [52]. In
other words, melatonin suppression effects in the older
adults are thought to be weakened as a result of theattenuation of ipRGCs stimulation due to filtering of blue
light caused by pupil diameter and lens transmittance
reduction [55]. Attenuation of melatonin suppression
in the older adults was also reported by Gabel et al. in2017 [56]. In their study, young subjects (mean ± SE age:
24.96 ± 0.58 years) and older subjects (63.58 ± 1.27 years)
were exposed to fluorescent light with an illuminance of
250 lx and color temperature of 2700 K (WL condition)and to fluorescent light with an illuminance of 250 lx andcolor temperature of 9000 K (BL condition) during sleep
deprivation. The younger subjects showed significant

Age‑related differences in melatonin suppression
Melatonin is a hormone that is biosynthesized in the pineal gland, and its production rhythm is regulated by the
SCN, a central biological clock, via pathways of the paraventricular nucleus, pre-sympathetic ganglion neurons,
superior cervical ganglion, and pineal gland [36]. Melatonin secretion shows a distinct circadian rhythm, withlittle secretion during the day, beginning at night, peaking at midnight and ending in the morning, making thesecretory rhythm a quantitative indicator of the phaseof the circadian rhythm. It is also known that melatoninsecretion is acutely suppressed by light exposure [37].
Melatonin suppression is induced when incident lightinformation from the eye reaches the SCN via retinal
ganglion cells containing the photopigment melanopsinthat contributes to non-visual effects (called mRGCs:
melanopsin-containing retinal ganglion cells, or ipRGCs:
intrinsically photosensitive retinal ganglion cells) andthen the pineal gland. The degree of suppression of melatonin secretion is often used as an indicator of non-visualphotosensitivity [10], and many studies have been conducted on age-related differences.
It is known that melatonin secretion itself also
decreases with age [38, 39], and there are individual differences in melatonin secretion even in the same agegroup [40]. In studies in which light-induced melatonin suppression was examined, the rate of melatonin
suppression was used with respect to an individual’s
melatonin concentration measured in a dim-light environment [37] or pre-exposure melatonin concentration[41] to exclude the effects of individual differences inmelatonin secretion. Therefore, differences in melatoninsecretion due to aging are expected to have little effecton differences in melatonin suppression rates. However,it may be necessary to examine how the light-induced
melatonin suppression affects physical and mental conditions not only in terms of the melatonin suppression but
also in terms of differences in secretion [38, 39, 42].
Melatonin suppression in the older adults

Regarding age-related differences in melatonin suppression, Herljevic et al. first reported results of a comparisonof melatonin suppression in young adults (mean age ± SD,
24 ± 3 years) and older adults (57 ± 5 years) in 2005 [43].
While there was no statistically significant difference inmelatonin suppression between the young and the older
adults after 30 min of exposure to green light (548 nm)(although suppression tended to be smaller in the older
adults), the older adults had significantly lower melatonin

Fig. 2 Crystalline lens transmittance spectra in vivo measured by
Purkinje image-based system [50]. The lens transmittance spectrum
in children is shown by a red line, that in young adults is shown by
a blue line, that in middle-aged adults is shown by a green line, andthat in the older adults is shown by an orange line. Depicted fromdata in Eto 2020 [50] and Eto 2021 [51]

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suppression of melatonin secretion in both lighting conditions (pronounced in the high color temperature BL
condition), whereas the older subjects showed no significant suppression in either lighting condition. A recent
study reported by Chellappa et al. in 2021 also showed
differences in melatonin suppression between older andyounger subjects [41]. Chellappa et al. compared melatonin suppression in three lighting conditions differing
only in color temperature (40 lx illuminance, 2500, 3000,
and 6500 K color temperatures) in young subjects (22–29 years old, average age: 25.2 years) and older subjects(58–70 years old, average age: 63.6 years). The results
showed that melatonin suppression occurred in both age
groups under all light conditions but that melatonin suppression only in the young group was enhanced under
the color temperature condition of 6500 K. The reason
why the enhancement of melatonin suppression in highcolor temperature light (6500 K) observed in young
subjects could not be confirmed in the older adult wasthought to be because the blue light component in highcolor temperature light was attenuated in the older adults
due to age-related lens opacity [41].
On the other hand, some studies have shown that melatonin suppression response is maintained in the older
adults. In 2014, Najjar et al. obtained spectral sensitivity curves of melatonin suppression using nine different
monochromatic lights and compared the curves in young
subjects (mean ± SE age: 25.8 ± 0.73 years) and older subjects (59.4 ± 0.99 years) [57]. Their results showed thatthe peak wavelength of the spectral sensitivity curve wassignificantly shifted toward longer wavelengths in theolder subjects but that there was no attenuation of melatonin suppression in the short-wavelength light region in
the older subjects [57]. The shift of the peak wavelength
toward longer wavelengths may be due to the effect oflight transmittance of the crystalline lens, but the factthat there was no significant difference in melatonin suppression in the short-wavelength light between the older
and young subjects does not support the results of theprevious study by Herljevic et al. [43]. Najjar et al. suggested that differences in transmittance of the crystalline lens, exposure light intensity and exposure duration
between those studies may have caused the discrepancy
in results. As for the maintenance of the melatonin suppression response in older adults, they speculated that
there might have been a compensatory function thatcompensated for the reduced light input to the retina.
The light sensitivity of non-visual functions has beenshown to be affected by recent changes in light history[31–33]. It has been reported that reduced daytime light
exposure in winter enhances melatonin suppression [27].
It has also been shown that wearing contact lenses thatblock short-wavelength light from 30 min before a 2-h

nocturnal light pulse until the end of the pulse attenuates
melatonin suppression, whereas after wearing the contact lenses for 16 days, melatonin secretion is suppressedto the same degree as that in the control condition [58].
In other words, attenuation of retinal illuminance associated with changes in crystalline lens transmittanceand pupil size in older adults can be viewed as changes
in long-term light history, which may have resulted inincreased (apparently maintained) light sensitivity asa physiological adaptation. On the other hand, Najjar
et al. [57] performed mydriatic procedures (pupil being
dilated) on their subjects, whereas the other studies [41,56] on melatonin suppression in older adults did not, andthis difference in methodology may also have led to discrepancies with the results of other studies.
Melatonin suppression in pre‑school children, school
children and adolescents

As mentioned above, there have been many studies on
age-related differences in the light-induced melatonin
suppression that were conducted using older subjects.
On the other hand, if pupil and crystalline lens characteristics affect age-related differences in the non-visual
effects of light, the light-induced melatonin suppression
would be expected to be stronger in populations withlarger pupils and high crystalline lens transmittance(such as young, school-age and adolescent children) thanin young adults.
Some studies on light-induced melatonin suppression
have also been conducted with children in childhood,early childhood, and adolescence. A study in young children (mean age: 4.3 ± 1.1 years) showed that melatonin
suppression also occurs robustly in young children,
although it is not clear whether there is childhood-specific light responsiveness because melatonin suppression
in young children was not compared with that in otherage groups [59]. In 2014, Higuchi et al. reported theresults of a comparison of melatonin suppression rates
in school children (8.6 ± 1.5 years old) and their parents(middle-aged: 41.2 ± 4.8 years old) [60]. The rate of melatonin suppression at habitual bedtime was approximately
1.9-times greater in the children than in the middle-aged
subjects (children: 88.2%, middle-aged subjects: 46.3%)
during exposure to white fluorescent light at an illuminance of 580 lx. Lee et al. in 2018 reported the results of acomparison of melatonin suppression in school children(8.9 ± 2.2 years) and middle-aged adults (41.7 ± 4.4 years)
exposed to two LED lighting conditions with illuminancefixed at approximately 300 lx and differing only in color
temperature (3000 and 6200 K) [61]. Melatonin suppression was significantly greater for the 6200 K lighting condition, which contains more blue components, than forEto and Higuchi ﻿Journal of Physiological Anthropology(2023) 42:11

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Fig. 3 Spectral irradiance distributions of 3000 K and 6000 K lighting conditions (A) and melatonin suppression in adults and children under eachlighting condition (B). Modified and adapted from Lee 2018 [61]the 3000 K lighting condition in children, whereas no
significant difference between the color temperature conditions was observed in the middle-aged subjects (Fig. 3;
Modified and adapted from Lee 2018 [61]). Enhanced
melatonin suppression in response to high color temperature lighting was also found in a study on adolescents[62].
The enhanced melatonin suppression response inchildren compared to that in middle-aged people [60]and the enhanced melatonin suppression in response tohigh color temperature light only in children [61] werealso thought to be due to age-related differences in pupil
diameter and lens light transmittance. However, it has
been difficult to investigate the relationship between
optical characteristics of the eye and melatonin suppression because there is no established methodology formeasuring crystalline lens transmittance (especially spectral transmittance), whereas measurement of pupil diameter is relatively easy. Recently, the authors developed asystem that can easily measure spectral transmittanceof the crystalline lens in vivo [50] and used it to investigate whether age-related differences in pupil size and lenstransmittance are related to the difference between melatonin suppression in school children and that in middleaged adults [51]. Melatonin suppression experiments
were conducted in school children (9.6 ± 1.8 years old)and middle-aged adults (41.2 ± 2.5 years old) exposed to
LED lighting with an illuminance of 300 lx and a color
temperature of 6000 K, and pupil diameter during thelight exposure and spectral transmission of the lens werealso measured. The pupil diameter and spectral transmittance of the lens were used to calculate non-visualphotoreception, which is an index of the influence of agerelated ocular changes on the non-visual photopigment
melanopsin, based on the method of Turner and Mainster[55], and the relationship between the age-related difference in non-visual photoreception and the age-relateddifference in melatonin suppression was evaluated. The
results showed that relative values of non-visual photoreception and melatonin suppression in children to adults
were 1.48 ± 0.08 (mean ± SE) and 1.52 ± 0.1, respectively,
and both values were almost matched. This suggests that,at least between school children and middle-aged adults,
age-related differences in pupil diameter and lens transmittance may influence the age-related differences inmelatonin suppression effects.
On the other hand, Crowley et al. reported that the lesssexually mature group (Pre/Mid-pubertal group) among
school-age children to adolescents (9–16 years old) had
stronger melatonin suppression responses than that in
the more sexually mature group (Late/Post-pubertal
group) [63]. Although it is difficult to generalize due tothe lack of information on pupil diameter and crystalline
lens transmittance, it is expected that there is no significant difference in pupil diameter or crystalline lens transmittance between the two groups, suggesting that factors
other than ocular optical characteristics may be responsible for the age-related difference in melatonin suppression during the developmental period.

Age‑related differences in circadian phase shift
Circadian rhythm is the rhythm of an approximately 24-h
cycle. Various circadian rhythms, such as sleep, bodytemperature and hormone secretion rhythms are regulated by the SCN, a central clock [64]. The endogenous
circadian rhythm of the human body is considered to beslightly longer than 24 h [65], and the circadian rhythm
cycle is synchronized to 24 h by the approach of ambient
light information, such as sunlight, on the SCN. Specifically, the phase of the circadian rhythm can be advanced(become morningness) or delayed (become eveningness)
depending on the timing of light exposure in a day. The
phase response curve (PRC) indicates in which direction (advance or delay) the phase of the circadian rhythm

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shifts and how much it shifts depending on the timingof light exposure in a day [19, 20]. However, it has beenreported that the phase response of the circadian rhythm
varies with age, even when exposed to light at the sametiming in the PRC.

by Duffy et al. study mentioned above, Sletten et al. suggested that the differences in the type of light (white fluorescent light or monochromatic light) and intensity may
have caused the difference in the results of the studies[71]. In addition to this, Sletten et al. performed mydriasis procedures on their subjects and this methodologicaldifference may also have contributed to the differences
between the results of the studies. More recently, in 2019,
Scheuermaier et al. in the research group of Duffy et al.
reported the results of an investigation of the amount ofcircadian phase delay in older subjects (58.3 ± 4.2 years
old) exposed to approximately 270 lx white light showing a minimum of phase delay of 0.9 h and a maximumof 3.2 h among the older subjects, a large individual variation [66].

Circadian phase shift in the older adults

In 2007, Duffy et al. investigated the dose–response
relationship between the illuminance of white fluorescent light (correlated color temperature: 4100 K) andthe amount of circadian rhythm phase delay (IRC: illuminance response curve [66]) in older subjects aged
65 years or older (mean ± SD age: 68.3 ± 4.7 years) [67].
The rhythm of melatonin secretion, a marker of the circadian rhythm phase, was delayed by a maximum of
about 3 h by light exposure during the biological night(a total of 6.5 h, from 30 min before habitual bedtime to
2 h before waking time). Duffy et al. compared the IRC
in older subjects with that already reported in younger
subjects aged 18 to 44 years (27.8 ± 8.9 years old) andfound that although there was no age-related differencein the minimum (at 0 lx) and maximum (at ~ 10,000 lx)
of phase delay, the illuminance that induced 50% of the
maximum phase delay was higher in the older subjects
than in the younger subjects (263 lx in the older subjects
and 119 lx in the younger subjects) [10]. The delay of circadian rhythm phases at extremely low and high levels of
illuminance is maintained in the older adults, in agreement with the results of previous studies [68, 69] and theresults of a recent study [70]. Therefore, the light-induced
shift effect of circadian rhythms is thought to be attenuated in the older adults in response to low to moderate
illuminance (approximately 50 to 1000 lx). Duffy et al.
suggested that senile constriction of the pupil and agerelated opacity of the lens may be responsible for attenuation of the light-induced circadian rhythm shift in theolder adults. As already mentioned, age-related reductions in pupil diameter and lens light transmittance in theblue light range are thought to attenuate the amount of
ipRGCs stimulation in the older adults.
On the other hand, in 2009, Sletten et al. compared the amounts of phase advance in young subjects(23.0 ± 2.9 years) and older subjects (65.8 ± 5.0 years)
during exposure to blue light (456 nm) and green light(548 nm) for 2 h in the morning (the timing of phaseadvance in PRC [20]), respectively [71]. Their results
showed that the amount of phase advance tended to begreater in the younger subjects than in the older subjects
when exposed to either blue or green light, but the difference was not statistically significant. Although the resultsof their study showing that these was no significant difference in the phase response between the older andyounger subjects do not support the results of the study

Circadian phase shift in children and adolescents

Although, as far as the authors know, there has been no
study in which the light responses of circadian rhythm
phase in populations even younger than young adults
were compared with these in other age groups, a PRC
of adolescents aged 14 to 17 years (16.2 ± 1.0 years old)
was shown by Crowley et al. in 2017 [72]. Crowley et al.
found that the maximum values of phase advance andphase delay were larger in the PRC of adolescents that in
the PRC of young adults reported by St. Hilaire et al. in
2012. However, they also noted that comparisons of themagnitude of phase shift between studies should be madewith caution because of several methodological differences including differences in the intensity, duration andmethod of light exposure.
Few studies have experimentally evaluated lightinduced circadian phase shifts in children. However, afield study has shown that camping life with much sunlight in the morning and little access to artificial lighting
at night advances circadian phases in children (age range,
9–14 years) [9]. The results of this study were similar to
those of Wright et al.’s study of the circadian phase shifts
in adults (30.3 ± 8.5 years old) during camping life [8].
However, it is not easy to discuss age-related differencesin light induced circadian phase shifts because thesestudies are not strictly environmentally controlled likelaboratory experiments.

Age‑related differences in pupillary light reflex
Light information from ipRGCs is also transmitted tothe pretectal olivary nucleus (PON), which is involvedin the pupillary light reflex [54, 73]. The pupillary lightreflex (PLR) refers to the increase or decrease in pupil
size between approximately 2 and 8 mm in diameter toregulate the amount of light incident on the retina, and it
is considered that vision over a wide range of brightness
can be maintained by controlling light intensity [74]. The

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PLR is mediated not only by ipRGCs but also by rods andcones. The proportion of contribution among ipRGCs,
rods and cones is known to depend on the intensity [75]and exposure time [76] of irradiated light. Specifically,
the contribution of cones and rods is predominant for
low-intensity incident light, whereas the contributionof ipRGCs is stronger for high-intensity incident light[75]. In addition, immediately after light exposure, thecontribution of cones and rods is large, but the proportion of their contribution decreases as the exposure timeincreases from tens to hundreds of seconds, and the contribution of ipRGCs becomes dominant [76]. It is usuallydifficult to extract only the responsiveness of ipRGCsfrom PLR independently of the cone and rod responses,
but the post-illumination pupil response (PIPR), in which
the pupil remains contracted even after the end of light
exposure (after the light stimulus is turned off ), is known
as a pupil response specific to ipRGCs [77]. PIPR has
been used in various studies as an index to evaluate thelight responsiveness of ipRGCs [78–81].

more ipRGCs, thereby enhancing PIPR [83]. On the other
hand, some studies have shown that PLR is attenuated in
the older adults [85, 87]. Rukmini et al. in 2017 compareddose–response curves of the pupil constriction rate andlight intensity when exposed to blue light (469 nm) andred light (631 nm) with various light intensities between
young (21–30 years old) and older (50 + years old) subjects [85]. Their results showed that there was no wavelength dependence in age-related differences in pupil
constriction, such as a particular attenuation for blue
light, but there were age-related differences in pupil contraction rate, especially for high intensity light. Therefore, Rukmini et al. speculated that the decrease in pupil
constriction, i.e., attenuation of the responsiveness of
the PLR, in the older adults is due not to the effect ofage-related changes in the crystalline lens but to aging
changes in the autonomic nervous system [88] and retina [89]. Experimental parameters, such as light stimuli
wavelength, intensity, and duration, in the studies mentioned in this section are summarized in Table 1.
As noted above, there is no unified view on whether
PLR is attenuated in the older adults compared to thatin young individuals. This may be related to the fact thatdifferent light intensities, wavelengths, and measurement
indexes were used in studies, and the results can therefore not be directly compared. The results also seem tovary depending on whether cataract patients are includedin the study [84, 85]. Recently, findings on PLR [85] and
PIPR [90] in cataract patients have been accumulating,and further studies are needed to determine whether PLR
is attenuated in the older adults, including the effects ofcataracts.

PLR in the older adults

In contrast to the attenuation of light-induced melatonin
suppression and circadian phase shift in the older adults,
it has been reported that PLR maintains its responsiveness to light in the older adults [78, 82–84], and that
although PLR is attenuated in the older adults, there is
no wavelength dependence in the attenuation despite
the fact that the short-wavelength light component
that reaches the retina is decreased [85]. According toa report by Daneault et al. in 2012, when older subjects(61 ± 4.4 years old) and younger subjects (22.8 ± 4.0 years
old) were exposed to blue light (480 nm) and green
light (550 nm), there was no significant age-related difference in the pupil contraction rate regardless of the
wavelength of light stimuli [82]. The studies by Kankipati
et al. [78] and Adhikari et al. [84] on age-related changes
in PIPR showed that there was no significant effect ofage on PIPR, suggesting that light responsiveness of thepupil may be maintained even in older individuals [78,84]. However, a study by Herbst et al. in 2012 showedthat PIPR to blue light was positively correlated withage, suggesting that aging may rather enhance pupillary
response [83]. Adhikari et al. discussed the discrepancy
in their results as being related to the fact that cataract
patients with lens opacity > grade 2 in LOCS III (lensopacities classification system III) [86] were excluded intheir study [84]. The report by Herbst et al. did not mention any exclusion criteria for subjects with lens opacities
and their study may have included older subjects withgrade 3 or higher in LOCS III [83]. They hypothesizedthat the clouding of the lens in cataract patients may
have increased the scattering component and stimulated

PLR in school children

Although there have been many studies in which PLR
age-related differences were compared in the older andyoung adults, there have been few studies in children.
We compared the spectral sensitivity of PLR between
school children (9.9 ± 1.2 years old) and young adults(22.1 ± 1.8 years old) to determine whether the higher
lens transmittance in children affects the age-related differences in PLR [91]. The results showed that the peakwavelength of the PLR spectral sensitivity curve tended
to differ between children and young adults and that thepeak wavelength shifts toward shorter wavelengths inchildren compared with that in young adults [91]. PIPR,
on ipRGC-derived pupillary response, was measured forthe first time in children (9.0 ± 1.8 years old) by Ostrin
in 2018 [92]. That study showed that the ipRGC-derived
pupillary response can be measured in children as
robustly as in adults [80], for whom PIPR has been previously measured. However, comparisons with other age

Dilated

44 healthy subjects aged between
26 and 68 years

60 young normal adults aged
21—30 years and 54 older adults
aged ≥ 50 years including mild
cataracts and severe cataracts

Rukmini et al. [85]2017

NOT dilated

NOT dilated

Stimuli condition

PIPR(Using average pupil size over a
period of 30 s, starting 10 s after
light offset)

There is no effect of age

Dark adaptation (< 6 lx): 10 min
Wavelength: Blue light (448 nm)
and red light (604 nm)
Intensity: Blue: 14.5 log quanta/
cm2/s; Red: 14.4 log quanta/cm2/s(corneal irradiance)
Duration: 1 or 10 s

Dose–response curve of PLR

Dark adaptation: 1 min
Wavelength: Blue light (469 nm)
and red light (631 nm)
Intensity: Gradually increase over
2 min from 6.8–13.8 log photons/
cm2/s
Duration: 2 min

Irrespective of wavelength, pupillary
responses were reduced in older
individuals and further attenuatedby severe, but not mild cataract

PLR (Maximal pupil contraction)
Dark adaptation (0 cd/m2):
Sustained pupil contraction andand PIPR (Sustained pupil contrac- 1 min after 4 min mesopic lighting AUC early correlated positively withtion, AUC early, AUC late)condition (0.74 cd/m2)
age
Wavelength: Blue light (470 nm)
and red light (660 nm)
Intensity: 3, 30, 100 and 300 cd/
m2 (corresponding irradiancewhen intensity is 300 cd/m2: Blue14.8 log photons/cm2/s; Red 14.9
log photons/cm2/s)
Duration: 20 s

No significant correlation was foundbetween PIPR and age

There was no difference between
age groups

Results

Dark adaptation: None mentioned*Interval between red and blue
stimuli was 5 min
Wavelength: Blue light (470 nm)
and red light (623 nm)
Intensity: 13 log quanta/cm2/s(estimated retinal irradiance)
Duration: 10 s

Steady-state PLR
Dark adaptation (0 lx): 15 min(Averaged pupil size during 39 s of before first stimulus; 2 minlight exposure)
between stimuli
Wavelength: Blue light (480 nm)
and green light (550 nm)
Intensity: Low: 7 × ­1012 photons/
cm2/s; Medium: 3 × ­1013 photons/
cm2/s; High: ­1014 photons/cm2/s
irradianceDuration: 45 s

Metrics

59 healthy subjects between ages Dilated and NOT dilated PLR (Transient PLR, peak pupilof 21 and 70 years. All participants
constriction) and PIPR (6 s PIPR,
had a lens grading of ≤ 2 in LOCS III
Plateau PIPR, AUC early, AUC late)

Herbst et al. [83]. 2012

Adhikari et al. [84]. 2015

Kankipati et al. [78]. 2010 37 normal subjects between agesof 19 and 80 years

16 young adults (22.8 ± 4 years
NOT dilatedold), and 14 older adults(61 ± 4.4 years old) including
subjects with level 2, 3 or 4 in LOCS
III [86]

Daneaut et al. [82]. 2012

Pupil condition

Subjects

Study

Table 1 Comparisons of experimental parameters in studies on PLR or PIPR in older adults

Eto and Higuchi ﻿Journal of Physiological Anthropology(2023) 42:11
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Eto and Higuchi ﻿Journal of Physiological Anthropology(2023) 42:11

Page 9 of 12groups have not been made, and it is not known whether
child-specific responsiveness exists in the PIPR.

several subtypes of ipRGCs have also been identified
in the human retina [114], and each subtype exhibits
distinct sensitivities and responses to light [115]. The
density of ipRGCs decreases with age, and it has beenreported that their decrease causes disturbances in bodytemperature and locomotor activity in rats [116], but astudy on the ipRGCs in the human retina has shown thatthe degree of decrease in the number of ipRGCs in thehuman retina appears to vary by subtype [117]. As wehave discussed, the effects of aging may differ dependingon the non-visual functions, such as circadian entrainment, melatonin suppression and PLR, and Daneault
notes that since these non-visual responses are mediated, at least in part, by different ipRGCs populations, itis plausible that the effects of aging differ [82]. Therefore,
age-related differences in each of these non-visual effects
would need to be assessed independently and with attention to the presence of ipRGCs subtypes.
Furthermore, if there are age-related differences in the
non-visual effects of light, further studies are needed todetermine the extents to which these age-related differences contribute to age-related differences in circadianclock function and sleep. In particular, from the viewpoint of physiological anthropology, it is important toclarify the effects of artificial lighting at night on various
aspects of human health such as sleep quality. In addition, individual differences [23, 24] as well as age-relateddifferences in non-visual functions are an important
topics as non-visual responses to light in individuals of
the same age depending on genotype [25, 26], season[27–29], ethnicity [30], and individual light exposure history [31–33]. Therefore, accumulation of data regarding
age-related and individual differences in the non-visual
effects of light as well as factors contributing to the differences in various age groups from children to the older
adults is important for designing and providing appropriate light environments, especially nighttime light environments, for humans, and further research is needed.

Conclusions
In this review, among the non-visual effects of lightin humans, studies on age-related differences in lightinduced melatonin suppression, circadian phase shift,and pupillary light reflex, including studies conductedby the authors, were reviewed. Whether or not there are
age-related differences in any of the non-visual functions
seems to be a matter of debate, since no unified view has
been reached due to differences in experimental conditions and methodologies. In addition, as factors contributing to age-related differences in non-visual functions,pupil diameter and crystalline lens transmittance weremainly discussed in this paper, but since various otherage-related factors such as differences in the numberof retinal ganglion cells [93], volume of the SCN [94],peptide expression (vasoactive intestinal polypeptide(VIP) [95, 96]; arginine vasopressin (AVP) [97]), densityof GABAergic synapses [98] and clock gene expression
in the SCN [99, 100] as well as differences in ophthalmologic characteristics are thought to be involved (seereview articles for details [101–104]), and the effects ofgrowth and aging on non-visual functions are expected
to be complex [34]. In order to study age-related differences in non-visual effects in detail, comparative studies should be conducted using subjects having a wide
range of ages with as much control as possible for intensity, wavelength component, duration, circadian timing, illumination method of light exposure, and otherfactors (mydriasis or non-mydriasis, cataracts or not in
the older adults, etc.). In addition to the cross-sectional
studies described above, longitudinal studies (although
not easy) are also necessary to better understand agerelated changes in the non-visual effects of light. Naturally, individual differences exist in the aging process,and the results of longitudinal studies would contributesignificantly to clarification of the development and aging
process of non-visual functions.
It is important to note that even if there are age-relateddifferences in one of the non-visual effects of light, it
does not necessarily mean that there are age-relateddifferences in other effects as well. For example, it has
been suggested that the light-induced melatonin suppression effects are functionally separate from the circadian rhythm phase shift effects [105]. Additionally,
there are several subtypes of ipRGCs, each with different
photosensitivity [106, 107] and projection brain regions(although some overlap) [108–110], and each mediates
different non-visual functions [111–113]. The studies
on the subtypes of ipRGCs have predominantly focusedon animal models, such as mice and rats. However,

List of abbreviations
LGN	Lateral geniculate nucleus
SCN	Suprachiasmatic nucleus
RHT	Retinohypothalamic tractmRGCs	Melanopsin-containing retinal ganglion cells
ipRGCs	Intrinsically photosensitive retinal ganglion cells
PRC	Phase response curve
IRC	Illuminance response curve
PON	Pretectal olivary nucleus
PLR	Pupillary light reflex
PIPR	Post-illumination pupil response
LOCS III	Lens opacities classification system III
VIP	Vasoactive intestinal polypeptide
AVP	Arginine vasopressin
Acknowledgements
Not applicable.

Eto and Higuchi ﻿Journal of Physiological Anthropology(2023) 42:11

Page 10 of 12

Author’s contributions
TE and SH had the original idea for the review study. TE contributed to theresearch, writing, and editing of this manuscript. SH contributed to the correction and editing of this manuscript. TE and SH read and approved the final
manuscript.

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Funding
This work was supported by JSPS KAKENHI Grant Numbers JP20H01659,
JP23H02569 and JP23K14278.
Availability of data and materials
Not applicable.

Declarations
Competing interests
The authors declare no competing interests.
Consent for publication
Not applicable.
Author details
1
Research Fellow of the Japan Society for the Promotion of Science, Kodaira,Japan. 2 Department of Sleep‑Wake Disorders, National Center of Neurology
and Psychiatry, National Institute of Mental Health, Kodaira, Japan. 3 Department of Human Life Design and Science, Faculty of Design, Kyushu University,
Fukuoka, Japan.
Received: 6 January 2023 Accepted: 15 June 2023

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